A  TEXT-BOOK 


PHAEMACOLOGY 


THEEAPEUTICS 


ACTION  OF  DRUGS  IN  HEALTH  AND  DISEASE 


BY 

ARTHUR  R.  CUSHNY,  M.A.,  M.D.,  LL.I).,  F.R.S. 

PBOFESSOR    OF    PHARMACOLOGY    IN    THE    UNIVERSITY    OF    LONDON;     EXAMINER    IN    THE 

UNIVERSITIES    OF    LONDON,    MANCHESTER,    OXFORD,    CAMBRIDGE,  GLASGOW    AND 

LEEDS;    FORMERLY    PROFESSOR    OF    MATERIA    MEDICA    AND    THERAPEUTICS 

IN    THE    UNIVERSITY    OF    MICHIGAN 


SIXTH  EDITION,  THOROUGHLY  REVISED 


ILLUSTRATED   WITH    70   ENGRAVINGS 


LEA   &   FEBIGER 

PHILADELPHIA   AND    NEW    YORK 


Kn(o'ic(l  accunlinu;  to  the  Act  of  Congress  in  I  he  year  1915,  by 

LEA   &   FEBIGKR, 
in  the  Ollifc  of  the  Librarian  of  Congress.     All  rights  reserved. 


Authority  to  use  for  comment  the  Pharmacopoeia  of  the  United  States  of  America 
(Eighth  Decennial  Revision),  in  this  volume,  has  been  granted  by  the  Board  of 
Trustees  of  the  United  States  Pharmacopoeial  Convention;  which  Board  of  Trustees 
is  in  no  way  responsible  for  the  accuracy  of  any  translations  of  the  Official  Weights 
and  Measures,  or  for  any  statement  as  to  strength  of  Official  Preparations. 


OSWALD  SCHMIEDEBERG 

DEM    MeISTER,  VOM   ScilULER   GEWIDMET 


ooazTu 


PREFACE  TO  THE  SIXTH  EDITION. 


In  this  edition  the  space  devoted  to  many  of  the  less  important 
and  less  reliable  drugs  has  been  further  curtailed  and  others  have 
been  omitted  altogether  from  consideration.  This  appears  to  be 
in  accordance  with  the  general  trend  of  medical  progress,  and  thera- 
peutics would  probably  not  have  suffered  from  an  even  more  drastic 
selection.  But  a  text-book  must  not  only  describe  the  virtues  of  the 
established  remedies,  but  must  also  point  out  the  worthlessness  of 
many  preparations  which  still  enjoy  an  unmerited  popular  reputation. 
I  would  appeal  to  teachers  and  especially  to  the  members  of  examining 
boards  to  restrict  further  the  drugs  which  the  student  has  to  study. 
For  as  long  as  he  has  to  learn  the  supposed  virtues  of  a  host  of  obscure 
substances,  he  will  tend  to  use  them  in  practice,  even  if  only  tentatively. 
This  in  turn  necessitates  their  inclusion  in  the  pharmacopoeias,  which 
again  gives  them  some  standing  and  perpetuates  them  as  subjects  of 
teaching  and  examination.  If  examiners  would  break  this  vicious 
circle,  they  would  greatly  lighten  the  burden  of  the  student,  and  would 
render  the  subject  of  pharmacology  more  attractive  to  him.  There 
is  no  question  that  the  insistence  on  numberless  preparations  of  drugs 
of  questionable  value  has  discouraged  interest  in  therapeutics. 

On  these  grounds  I  have  omitted  many  preparations  which  are 
still  to  be  found  in  the  pharmacopoeias,  but  which  appear  to  me  to  be 
superfluous.  Some  chapters  have  been  much  curtailed,  others  recast  and 
expanded,  all  have  been  carefully  revised.  Among  those  which  have 
been  much  altered  are  the  chapters  on  the  general  anesthetics,  opium, 
digitalis,  ergot,  and  adrenaline.  Several  new  chapters  have  been  added, 
among  them  those  on  the  new  organic  arsenical  compounds,  on  atophan 
and  on  the  pituitary  extract.  Extensive  changes  have  been  made 
in  the  classification,  which  is  now  based  on  the  organs  on  which 
the  drugs  exercise  their  most  characteristic  action  rather  than  on  a 
consideration  of  the  whole  of  their   effects.     This   new   arrangement 


vi  PREFACE 


honrs  a  closer  relation  to  the  therapeutic  uses  than  that  adopted  in 
former  editions.     A  large  number  of  drugs  chiefly  used  for  their  local 
action  as  antiseptics  and  dishifectants  has  heen  collected  into  one  group         j 
and  discussed  together.    I  hope  that  these  changes,  which  T  have  found      _ 


useful  in  my  own  classes,  may  prove  acceptable  to  others. 

A.  U.  C 
London,  10  lo. 


1 

i 


CONTENTS. 


Introduction 1' 

(iciicral  Theories  of  Pharniacological  Action 19 

Stinnilation,  Depression,  Irritation .21 

Distribution  and  Concentration .22 

Elective  Affinity  of  Drugs.     Protoplasm  Poisons  23 

Remote,  Local,  and  General  Action .24 

Salt-action 25 

Conditions  Modifying  the  Effects  of  Drugs 27 

Metliods  of  Administration 32 

The  Chemical  Characters  of  Drugs .36 

The  Pharmacopoeias  and  Pharmacopa-ial  Preparations 39 

PART  I. 

SUBSTANCES  WHICH  ARE  CHARACTERIZED  CHIEFLY  BY  THEIR 

LOCAL  ACTION .43 

I.  Demulcents 43 

II.  Emollients .46 

III.  Sugars  and  Flavoring  Substances  49 

IV.  Simple  Bitters 51 

Pepper  Group 53 

V.  Digestive  Ferments 54 

1.  Pepsin 5o 

2.  Pancreatic  Ferments 55 

3.  Vegetable  Ferments 56 

4.  Diastase 57 

VI.  Volatile  Oil  Series 57 

1.  Volatile  Oils  Used  as  Flavoring  Agents  and  Carminatives   .  61 

2.  Camphor 65 

3.  Ether  and  Chloroform  (Local  Action) 69 

4.  Malodorous  Volatile  Oils 71 

VII.  Skin  Irritants  and  Counter-irritation 72 

1.  The  Turpentine  Oil  Group 80 

2.  Mustard 82 

3.  Cantharidin  Series 83 

VIII.  Purgatives 87 

1.  Mild  Aperients,  the  Castor  Oil  Group 90 

2.  The  Anthracene  Purgatives 93 

3.  The  Jalap  and  Colocynth  Group                                                    .96 
IX.  Saline  Cathartics 101 

X.  Vegetable  Astringents — Tannic  Acid  Series 109 

XI.  Bile 114 


\111 


COXTKXTS 


XII.  AiiLlicliiiintics 

1.  Male  Fcni  (Asi)itliuin,  I'ilix-masj 

2.  Cusso 

3.  Pelletierine 

4.  Thymol 

5.  Santonin 

XIII.  Antiseptics  and  Disinfectants 

I.  Surgical  Antiseptics  and  Disinfectants 

1.  Carbolic  Acid 

2.  Cresols    ...  .... 

3.  Other  Aromatic  Surgical  Disinfectants 

4.  Mercuric  Perchloride    .... 

5.  Other  Metallic  Disinfectants 
(5.  Oxidizing  Disinfectants 

Peroxide  of  Hydrogen 

Other  Oxidizing  Disinfectants 

7.  Boracic  Acid  and  Borax    . 

8.  Potassium  Chlorate      .... 

9.  Iodine 

10.  Iodoform 

II.  Antiseptics  Used  Chiefly  in  Skin  Diseases 

1.  Pyrogallol 

2.  Chrysarobin 

3.  Naphthol 

4.  Resorcin 

5.  Tar 

III.  Intestinal  Disinfectants 

Salol 

Other  Intestinal  Disinfectants 

IV.  Gcnito-urinary  Antiseptics       .... 

1.  Volatile  Oils 

2.  Hexamcthylentetraminc,  I'rotropine 

3.  Minor  Genito-urinary  Antiseptics 
V.  Antiseptics  in  Pulmonary  Disease 

Creosote      

VI.  Disinfectants  for  Rooms,  Furniture,  Etc. 

1.  Formaldehyde 

2.  Sulphur  Dioxide 

3.  Chlorine  and  Bromine 

4.  Other  Disinfectants      .... 


11.5 
IK) 
IIS 
110 
120 
121 
124 
131 
131 
137 
138 
139 
139 
140 
140 
142 
143 
14.5 
149 
149 
1."j2 
1.52 
153 
154 
1.55 
155 
157 
157 
158 
158 
158 
160 
161 
1()2 
102 

It;:; 
Ki:; 
165 
166 
168 


PART  II. 


SUBSTANCES    CHARACTERIZED    CHIEFLY    \\\      IlIKIH    ACTION 

AFTER  ABSORPTION 1()9 

I.  Narcotics  of  the  Methane  Series 169 

Alcohol-chloroform  Grouj)        16".» 

1.  Alcohol 172 

2.  General  Anicsthetics — Ether  and  C'liloroforin 195 

3.  Nitrous  Oxide 221 

4.  Soporifics — Chloral  Group  228 
11.  ( )|)iiiin  Scries 236 

MiuDF  Drug.s  of  the  Opium  Series  -'  >~ 


CONTENTS  IX 

III.  Caiinahis  liulica 258 

IV.  Bromides ^^ 2()0 

V.  Strychnine — Nux  Vomica 2(56 

VI.  Picrotoxin 277 

VII.  Caffeine    ^ 280 

Coffee  and  Tea 289 

Minor  Diuretics 291 

VIII.  Saline  Diuretics 292 

Peripheral  Nervous  Action 295 

IX.  Curara  Group 298 

Coniine 302 

Gelsemium 303 

Sparteine 303 

X.  Nicotine  Group 304 

Tobacco 312 

XI.  The  Atropine  Series 314 

Alkaloids 330 

Agaricin 335 

XII.  Pilocarpine  and  Muscarine 336 

XIII.  Physostigminc 345 

XIV.  Cocaine 350 

Substitutes  for  Cocaine 361 

Yohimbine 363 

XV.  Adrenaline 364 

XVI.  Ergot 373 

XVII.  Pituitary  Extract 381 

Other  Organic  Extracts  (Organotherapy) 384 

XVIII.  Hydrastine  and  Hydrastinine 385 

XIX.  The  Nitrites 387 

XX.  The  Digitalis  Scries 395 

XXI.  Aconitine 425 

XXII.  Veratrine 430 

XXIII.  Apomorphine 434 

XXIV.  Emetine  (Ipecacuanha) 437 

XXV.  Colchicine 440 

XXVI.  Phenylquinohnc  Carbonic  Acid  (Atophan) 443 

XXVII.  Saponin,  Sapotoxin  and  Solanine 445 

XXVIII.  Prussic  Acid 449 

XXIX.  Aspidosperma,  or  Quebracho 454 

XXX.  Quinine 455 

XXXI.  The  Antipyretics  (Acetanihde  and  Antipyrine  Series)     ....  470 

XXXII.  Salicylates 485 

XXXIII.  Toxins  and  Antitoxins 494 

Antidiphtheritic  Serum 496 

Antitetanus  Serum 497 

Antimeningitis  Serum 497 

Antivenin 498 

XXXIV.  Benzoic  Acid .499 

XXXV.  Some  Minor  Poisons 502 

1.  Nitrobenzol  Compounds 502 

2.  Toluylendiamine 503 

3.  Benzol 503 

4.  Phloridzin 504 


X  ('<K\T  K:\rS 

XXWJ.  SchUuiii  ("hloi-idu  and  Water      .      .  505 

XXX VI I.  I'otassiiiin  Salts 513 

Lithium,  Caesium,  llubidiuin  515 

XXXVIII.  Ammonium 515 

XXXIX.  Iodides 518 

XL.  Iodine 525 

XLI.  Thyroid  Gland     ....  527 

XLII.  Sulpliitos 5:>5 

XLIII.   Hydrates  and  (.'ari)onates  of  the -Mkalie.s  5oG 

Pipcrazine  and  Quinic  Acid 545 

XLIV.  Acetates  and  Citrates 5 15 

XLV.  Ammonia  and  Carbonate  of  Ammonia 54G 

XLVI.  Acids 549 

XLVII.  Calcium 55G 

XLVIII.  Oxalates  ami  Fluorides 565 

XLIX.  Barium,  Strontium,  and  Maj^nesiuni    .      .  5(»() 

L.  Sulphides 5(i.S 

LI.  Charcoal 570 

LII.  Carbonic  Acid 571 

LIII.  O.xygen 574 

LIV.  Phosphorus 57(5 

LV.  Arsenic 587 

LVI.  Organic  Ar.senic  Combhiations (j02 

1.  Cacodylatcs ()04 

2.  Ato.\yl 004 

3.  Salvarsan 005 


PART  III. 

THE  HEAVY  METALS     .  (ill 

Heavy  Metals Oil 

I.  Antimony 018 

II.  Mercury (522 

III.  Iron fill) 

IV.  Lead 050 

V.  Cop[)er 058 

VI.  Zinc 0ti2 

VII.  Silver 001 

Vlll.   Hisnmtli 000 

IX.  Aluminium  and  Alum 072 

X.  Minor  Metals 074 


PART  IV. 

I.  Cod-liver  Oil 081 

lIypoj)h()spiiites  and  (ilj'cerophosphates 081 

11.    .Menstrua  and  Me(^liaiiical  Remedies <'>8  1 


CLASSIFIC  A'llON  OF  DRUGS  ACCORDING  TO  THEIR  T11ER.\PEIT1C 

I'SES 087 

I.NUE.X 003 


A  TEXT-BOOK  OF  PHARMACOLOGY. 


INTRODUCTION. 

Pharmacology  is  the  study  of  the  changes  induced  in  living  organ- 
isms by  the  administration  in  a  state  of  minute  division  of  such  un- 
organized substances  as  do  not  act  merely  as  foods.  Many  of  the  best 
known  of  these  substances  are  used  to  counteract  the  effects  of  disease, 
or  to  reinforce  the  tissues  in  their  struggle  to  maintain  their  functions, 
when  these  are  rendered  abnormal.  These  substances  are  known  as 
drugs,  and  the  art  of  applying  drugs  in  disease  is  Therapeutics.  Other 
substances  are  of  little  or  no  value  in  disease,  but  are  of  importance 
because  they  act  as  yoisons,  that  is,  cause  dangerous  or  fatal  symptoms 
in  man  or  animals,  when  they  are  ingested  in  quantity.  The  practical 
study  of  the  effects  of  these  poisons  in  man — the  diagnosis  and  the 
treatment  of  poisoning,  and  the  methods  of  detecting  the  poison — is 
termed  Toxicology.  But  the  explanation  of  the  symptoms  induced 
by  chemical  substances  belongs  to  the  field  of  pharmacology,  which 
includes  not  only  the  effects  of  drugs  and  poisons,  but  those  of  any 
substance  which  induces  changes  in  the  living  organism,  whether  those 
changes  are  of  benefit  to  it,  injurious,  or  indifferent.^ 

_  The  substances  must,  of  course,  conform  to  the  requirements  of  the  defini- 
tion._  Thus,  a  needle  introduced  into  the  tissues  induces  effects  which  are 
outside  the  field  of  pharmacological  investigation,  because  it  is  not  in  a  state 
of  minute  division.  But  the  iron  of  the  needle  may  be  reduced  to  a  fine 
powder  and  induce  changes  in  the  body  which  are  then  the  legitimate  subject 
of  research.  Similarly  the  drug  must  be  introduced  from  without,  for  many 
active  agents  are  formed  within  the  body,  but  their  study  belongs  rather  to 
the  departments  of  physiology  and  pathology;  and  the  effects  of  organized 
bodies  introduced  from  without  are  now  studied  under  bacteriology.  Phar- 
macology is  really  a  department  of  biology,  very  closely  related  to  the  other 
sciences  included  by  that  term.  Thus,  as  physiology  is  the  study  of  the  life 
of  the  normal  organism,  pharmacology  is  the  study  of  the  organism  rendered 
abnormal  by  drugs,  while  in  pathology  the  phenomena  of  life  under  disease 
are  examined.  All  three  subjects  may  be  pursued  without  reference  to  the 
practical  needs  of  medicine,  and  all  three  are  closely  interconnected  and 
mutually  dependent,  for,  in  many  instances,  the  normal  condition  of  an  organ 
can  be  recognized  only  by  considering  the  results  of  its  destruction  by  disease 

'  It  is  quite  impossible  to  distinguish  between  drugs  and  poisons.  Almost  all  remedies 
given  in  excess  cause  dangerous  or  fatal  symptoms,  while  many  poisons  are  valuable 
remedies  in  small  doses.  Some  bodies  may  in  fact  be  remedies,  foods,  or  poisons  accord- 
ing to  the  quantity  ingested  and  the  method  of  application. 

2  M7  1 


18  l.WTRODUCTION 

(patliolosy),  or  of  its  paralysis  or  stimulation  by  chemical  agents  (pharma- 
cology). .Similarly,  many  of  the  features  of  disease  are  now  recognized  to  be 
due  to  the  presence  of  unorganized  poisons  formed  in  and  bj'  the  tissues,  and 
it  accordingly  becomes  difficult  to  define  accurately  the  limits  of  pathology 
and  pharmacolog}'. 

The  great  interest  of  pharmacology  does  not  lie  in  its  purely  bio- 
logical aspects,  however,  hut  in  its  relation  to  the  treatment  of  disease. 
As  long  as  we  are  ignorant  of  how  a  remedy  acts  in  any  disease,  the 
treatment  is  purely  empirical;  when  the  mode  of  action  is  understood, 
nuich  greater  accuracy  can  be  attained  in  the  treatment.  The  object 
of  pharmacology  is  to  explain  the  mysteries  of  therapeutics,  whether 
the  subject  is  studied  at  the  bedside  or  in  the  laboratory.  The  exact 
way  in  which  a  drug  changes  the  diseased  condition  can  often  be  followed 
only  imperfectly  in  man,  and  recourse  must  be  had  to  experiments  on 
healthy  or  diseased  animals  to  elucidate  the  principles  on  which  it 
should  be  employed.  In  addition,  the  experimental  investigation  of 
new  chemical  bodies  has  very  frequently  demonstrated  properties 
which  are  of  therapeutic  value;  almost  all  the  new  drugs  introduced 
in  the  last  half-century  have  found  their  way  to  the  wards  through  the 
experimental  laboratories. 

Pharmacology  is  one  of  the  most  recent  developments  of  medical  and 
biological  science.  It  is  true  that  from  the  earliest  times  attempts 
have  been  made  to  explain  the  effects  of  drugs  on  the  then  prevailing 
theories  of  pathology,  but  the  objective  study  of  the  action  of  drugs  on 
the  organism  has  been  a  development  of  the  nineteenth  century,  or  it 
might  almost  be  said,  of  the  second  half  of  it.  The  study  of  drugs  was 
termed  Materia  Medica  up  to  this  time,  and  comprised  an  examination 
of  their  botanical  and  chemical  properties  along  with  some  account  of 
the  diseases  in  which  they  had  proved  of  value.  This  descriptive 
rather  than  experimental  study  has  been  continued  under  the  name  of 
Pharmacognosy,  but  is  now  pursued  by  pharmacists  chiefly.  Undoubt- 
edly the  student  of  medicine  ought  to  know  those  characters  of  drugs 
which  are  of  importance  in  modifying  their  action  and  application, 
but  it  is  undesirable  that  his  valuable  time  should  be  occupied  in  the 
detailed  description  of  crude  substances,  which  he  may  probably  never 
have  an  oj)portunity  of  seeing  in  his  future  practice. 

Another  subject  which  now  occupies  a  much  less  prominent  position 
in  medical  study  than  formerly,  is  Pharmacy,  or  the  art  of  preparing 
drugs  for  therapeutic  use.  Some  general  kiunvledge  of  the  methods 
used  is  no  doubt  indispensible  to  the  educated  i)hysician,  but  the 
details  may  be  left  to  the  pharmacist.  Pharmacy  will  probably 
occupy  a  still  more  subordinate  position  in  metlical  education  as  the 
tendencx'  to  include  only  one  or  two  drugs  in  a  prescription  becomes 
more  widesjjread.  As  long  as  a  dozen  or  more  com])onents  went  to 
make  one  mixture,  it  was  of  importance  to  know  their  solubility  and 
their  interactions,  but  with  the  decay  of  the  comj)lex  prescription 
the  study  of  j)harmac\'  by  nu'dical  students  has  certainly  become  less 
imperatixe. 


GENERAL  rilEORlES  OF  PHARMACOLOGICAL  ACTION  19 


GENERAL  THEORIES  OF  PHARMACOLOGICAL  ACTION. 

A  number  of  drugs  affect  tlie  organism  only  througli  their  obvious 
physical  properties,  as  wlien  an  inert  oily  body  is  applied  to  an 
abraded  surface  and  promotes  its  healing  by  protecting  it  from  irrita- 
tion and  from  the  evaporation  of  fluid,  or  when  common  salt  absorbed 
into  the  blood  changes  its  osmotic  tension,  and  thus  alters  the  distri- 
bution of  fluids  in  the  tissues.  On  the  other  hand,  many  effects  are 
due  to  simple  chemical  reactions;  for  instance,  bicarbonate  of  potas- 
sium may  be  used  to  neutralize  the  hydrochloric  acid  of  the  gastric 
juice,  just  as  it  combines  with  acid  in  a  test-tube,  and  many  of  the 
effects  of  oxalates  arise  from  their  forming  insoluble  salts  with  the 
calcium  of  the  tissues.  In  the  great  majority  of  drug  effects,  however, 
no  such  simple  relations  as  these  obtain  and  the  mode  of  action  remains 
unknown.  One  view  which  has  been  widely  held,  postulates  that  where 
a  drug  affects  a  cell  it  enters  into  a  definite  chemical  combination  with 
the  constituent  protoplasm,  similar  to  the  ordinary  compounds  of  the 
chemical  laboratory.  This  theory  has  not  been  supported  by  evidence, 
and,  while  it  has  not  been  disproved,  there  are  many  difficulties  in  its 
acceptance;  one  of  these  is  that  the  same  action  may  be  induced  by  a 
series  of  drugs  which  have  no  chemical  reactions  in  common  and  which 
therefore  cannot  be  supposed  to  enter  into  the  same  chemical  combina- 
tion with  the  cell  protoplasm.  In  recent  years  there  has  been  a  tendency 
to  attribute  the  action  of  drugs  rather  to  their  physical  properties,  and 
there  can  be  no  question  that  these  play  a  large  part  in  determining 
the  effects;  for  example,  unless  a  drug  is  soluble  in  the  fluids  of  the  body 
it  cannot  be  absorbed  and  circulate  in  the  blood,  and,  similarly,  unless 
it  is  soluble  in  the  cell  contents  it  may  have  difficulty  in  entering  the 
cells.  Many  drug  effects  have  been  ascribed  to  this  selective  absorption 
alone,  a  drug  acting  on  all  cells  into  which  it  can  enter,  by  changing  the 
relations  of  the  cell  constituents  in  which  it  is  dissolved;  but  objections 
have  been  raised  to  this  view  which  cannot  be  neglected.  (See  Meyer- 
Overton  theory  of  narcosis.)  Similarly,  attention  has  been  drawn  to 
the  possibility  that  some  effects  may  arise  from  the  drugs  altering  the 
surface  tension  of  a  cell  in  relation  to  the  surrounding  fluids.  It  has 
been  shown  that  in  some  cases  in  which  true  chemical  combinations 
were  believed  to  be  formed  between  cell  constituents  and  drugs,  the 
connection  is  really  of  the  loose  natureknown  as  "adsorption  compounds," 
which  are  best  illustrated  in  the  combination  of  dyes  with  fibres 
(see  Heavy  Metals) ;  the  formation  of  these  adsorption  compounds  is 
associated  with  a  change  of  electrical  charge  and  some  authorities 
are  disposed  to  attribute  some  other  pharmacological  actions  to  a  similar 
change  in  electrical  state.  Finally,  it  is  believed  that  in  most  instances 
drugs  act  on  a  cell  only  when  they  have  penetrated  into  its  interior, 
but  the  virtues  of  certain  remedies  have  been  shown  to  be  due  to  their 
failure  to  penetrate  the  cells,  which  leads  to  an  alteration  in  the  relation 
of  the  fluids  in  which  they  are  dissolved  and  those  in  the  interior  of  the 


20  INTRODUCTION 

cells  with  which  they  are  in  contact  (see  Salt-action).  And  Straub  has 
brought  forward  some  evidence  that  certain  very  powerful  drugs  act 
by  altering  the  cell  surface  without  penetrating  into  the  interior,  while 
others  effect  changes  only  as  they  penetrate  the  surface,  and  lose  their 
efficiency  as  they  accumulate  in  the  interior.  Changes  in  the  intra- 
cellular membranes  have  been  suggested  by  others  as  an  explanation 
of  most  drug  efi'ects;  it  is  held  that  a  drug  may  reduce  the  permeability 
of  the  cellular  membranes  by  altering  their  electric  charges  and  thus 
retard  the  free  passage  of  ions  which  is  necessary  for  full  activity; 
other  poisons  may  accelerate  their  movement,  and  thus  increase  the 
activity. 

These  views  have  all  been  supported  by  a  certain  amount  of  evidence, 
and  there  is  every  reason  to  believe  that  these  physical  properties  are 
important  factors  in  the  action  of  some  drugs.  But  it  is  equally  obvious 
that  no  one  of  them  will  explain  the  whole  of  pharmacological  action, 
and  there  is  reasonable  doubt  whether  the  whole  of  the  physical  char- 
acters taken  together  will  suffice  for  this.  From  the  present  confusion 
the  only  legitimate  conclusion  seems  to  be -that  the  activity  of  drugs 
depends  on  a  large  variety  of  factors  and  that  pharmacological  action 
cannot  be  brought  under  any  one  law,  either  chemical  or  physical. 

This  view  stands  in  conflict  with  a  theory  which  has  been  widely 
held,  and  which  postulates  that  the  pharmacological  action  depends 
directly  on  the  chemical  structure  of  a  drug  and  may  in  fact  be  deduced 
in  large  part  from  a  consideration  of  its  structural  formula.  Plausible 
arguments  in  favor  of  this  view  have  been  drawn  from  the  resemblances 
in  action  presented  by  certain  chemical  groups;  for  example,  a  large 
number  of  soporifics  belong  to  the  group  of  the  simpler  methane  com- 
pounds, and  the  heavy  metals  offer  certain  resemblances  in  their  effects 
in  the  body  just  as  they  react  similarly  to  some  chemical  tests.  But 
it  is  equally  probable  that  these  resemblances  depend  on  some  physical 
property  which  is  common  to  each  group,  and  which  has  a  more  imme- 
diate bearing  on  their  action  than  the  actual  structure.  Of  course  the 
physical  characters,  themselves,  ultimately  depenil  on  the  chemical 
composition,  and  the  reaction  in  the  organism,  therefore,  ultimately 
arises  from  the  chemical  composition,  but  as  it  is  at  present  impossible 
to  derive  the  physical  properties  from  a  consideration  of  the  chemical 
formula,  it  aj^pears  futile  to  attempt  to  derive  the  action  in  the  organ- 
ism from  it.  And  wjK'ne^'('ran  attempt  is  made  to  follow  the  relationship 
between  chemical  composition  and  i)harmac()logicaI  action  in  detail,  the 
analogy  l)reaks  down,  because  factors  which  it  is  impossible  to  deduce 
from  the  chemical  structure  or  formuhv,  intrude  themselves;  for  example, 
the  series  of  lower  alcohols  of  the  methyl  series  show  a  regular  progressive 
increase  in  toxicity  so  that  some  of  the  higher  members  might  be 
expected  to  form  very  powerful  poisons,  but  as  a  matter  of  exi)criencc 
these  prt)\e  to  be  harmless  because  they  become  insoluble  in  the  lluids 
of  the  bod  v. 


STIMULATION,  DEPRESSION,  IRRITATION  21 

STIMULATION,  DEPRESSION,  IRRITATION. 

When  a  cell  is  affected  by  a  poison,  the  extent  of  its  activity  is 
changed  but  not  the  kind.  The  reflex  movements  may  be  augmented 
under  strychnine  or  may  be  lessened  under  chloral,  but  they  remain 
reflex  and  cannot  under  any  circumstances  partake  of  the  nature  of 
voluntary  movements.  In  other  words,  the  effects  of  drugs  are  quan- 
titative, not  qualitative,  the  activity  of  living  matter  may  be  changed, 
but  the  form  which  the  activity  assumes  is  unchangeable. 

Drugs  which  increase  the  activity  of  any  organ  or  function  are  said 
to  stimulate  it,  while  those  which  lessen  the  activity  are  said  to  depress 
it.  Another  condition  induced  by  drugs  is  irritation,  for  although  this 
term  is  often  applied  loosely  as  a  synonym  for  stimulation,  the  two 
conditions  are  not  identical.  Stimulation  is  properly  used  to  indicate 
an  increase  in  the  specialized  function  of  a  cell,  producing,  for  instance, 
in  the  spinal  cord  an  increase  in  the  reflex  excitability.  Irritation, 
on  the  other  hand,  is  used  rather  in  reference  to  the  changes  in  the 
conditions  common  to  all  forms  of  living  matter,  that  is,  it  indicates  a 
change  in  the  nutrition  and  growth  of  the  cell,  rather  than  in  the 
specialized  functions.  Irritation  may  thus  be  induced  in  all  kinds 
of  tissues  and  is  the  commonest  change  caused  by  drugs  in  the  less 
differentiated  forms,  such  as  the  connective  tissues  and  ordinary 
epithelia;  while  stimulation  is  met  with  in  the  more  highly  specialized 
cells,  such  as  those  of  the  heart,  nervous  system,  or  secretory  glands. 
In  many  instances  the  irritant  action  of  drugs  may  be  explained  by 
their  known  reactions  with  the  proteins  of  the  cell;  for  example,  sub- 
stances which  dissolve  proteins,  or  precipitate  them,  or  withdraw  fluid 
from  them,  all  tend  to  cause  irritation  when  they  are  applied  to  living 
tissues.  In  other  cases  irritation  appears  to  be  induced  through  some 
action  the  nature  of  which  is  quite  vmknown. 

When  stimulation  is  prolonged  or  excessive,  the  protoplasm  gener- 
ally becomes  depressed  and  finally  loses  its  activity  entirely  (paral- 
ysis). Some  authorities  have  asserted  that  depression  is  invariably 
preceded  by  stimulation,  and  that  stimulation  sufficiently  prolonged 
invariably  leads  to  depression  and  paralysis.  Both  statements  are  too 
absolute,  although  they  are  true  in  the  great  majority  of  cases.  For 
example,  the  action  of  atropine  on  the  terminations  of  the  cardiac 
inhibitory  nerves  is  purely  depressant.  Even  the  most  minutg  quan- 
tities of  this  alkaloid  never  increase  the  activity  of  these  termi  ations, 
for  if  a  quantity  too  small  to  weaken  them  is  ingested,  it  has  appar- 
ently no  effects  whatever,  and  as  the  dose  is  increased,  the  first  effec 
is  depression. 

Depression,  whether  induced  directly,  or  following  on  stimulation, 
has  been  shown  in  several  instances  to  resemble  the  fatigue  induced 
by  the  prolonged  exercise  of  the  normal  organ,  and  it  is  probably  true 
that  depression  and  fatigue  are,  in  all  instances,  identical  in  appear- 
ance, although  not  necessarily  identical  in  cause.  For  example,  the 
phenomena   of  fatigue   of  the   terminations    of  the   motor   nerves  in 


22  INTRODUCTrOX 

muscle  resemble  exactly  those  induced  by  curara,  but  in  the  former 
the  cause  may  be  that  the  couductinj^  substance  of  the  nerve  ends  has 
been  used  up  by  the  repeated  passage  of  impulses,  while  in  the  latter 
.the  conductin<!:  substance  is  so  changed  that  it  becomes  incapable  of 
transmitting  stinuili  to  the  muscles.  The  final  result  is,  of  course, 
the  same;  there  being  no  available  conducting  substance,  impulses 
fail  to  reach  the  muscle.  But  the  fatigued  terminations  rapidly 
recover,  as  conducting  substance  is  reformed,  wliile  the  curarized 
recover  only  when  the  poison  is  eliminated. 

In  most  cases  an  excessive  dose  of  a  stimulating  poison  leads  to 
depression  and  paralysis.  The  cell  becomes  functionally  dead,  but  if 
the  failure  of  its  function  does  not  involve  the  death  of  the  organism, 
it  may  recover  and  reassume  its  ordinary  function  as  if  no  stage  of 
inactivity  had  intervened.  Excessive  irritation,  on  the  other  hand, 
leads  to  actual  death  and  disintegration,  from  which  there  is  no 
recovery.  For  example,  the  cells  of  the  spinal  cord  are  first  stimu- 
lated and  later  paralyzed  by  a  large  dose  of  strychnine,  but  this  is  not 
fatal  to  cold-blooded  animals,  and  after  a  few  days  the  spinal  cord 
regains  its  normal  function,  as  the  poison  is  eliminated.  On  the  other 
hand,  the  injection  of  an  irritant  into  the  subcutaneous  tissues  causes 
dilatation  of  the  vessels,  effusion  of  fluid,  and  increased  growth  and 
rapid  division  of  the  cells.  If  only  a  small  quantity  be  injected,  this 
condition  is  recovered  from,  although  it  generally  leaves  evidence  of 
its  presence  in  the  form  of  an  increase  in  the  fibrous  tissue.  But  if 
the  irritation  be  intense,  the  cells  undergo  degeneration  and  die,  and 
an  abscess  is  formed.  The  cells  thus  destroyed  can  never  recover  as 
the  paralyzed  ones  do.  They  are  either  absorbed,  or  removed  by  the 
opening  of  the  abscess,  and  their  room  is  filled  by  the  overgrowth  of 
the  neighboring  tissues. 

DISTRIBUTION  AND  CONCENTRATION. 

The  distribution  t)f  a  drug  in  the  different  tissues  and  organs  of  the 
body  must  influence  its  action;  and  it  might  be  expected  that  those 
organs  which  contain  it  in  largest  proportions  would  show  greater 
changes  than  others  in  which  it  is  present  in  smaller,  amounts.  But  this 
is  not  found  to  be  true  in  many  instances;  for  example,  the  liver  often 
contains  larger  quantities  of  alkaloids  than  any  other  tissue,  yet  no 
symi)toms  may  arise  from  this  organ.  The  relative  concentration  in 
which  a  drug  is  present  in  the  different  tissues  thus  does  not  determine 
the  extent  to  which  these  are  involved  in  the  action.  But  if  an  organ 
reacts  to  a  drug,  the  degree  of  its  reaction  depends  on  the  concentration 
in  which  the  drug  is  presented  to  it  and  the  i)roblem  in  therapeutics 
is  very  generally  to  bring  up  the  concentration  in  one  organ  to  the 
efficient  threshold  without  involving  other  organs;  for  example,  in 
chloroform  anesthesia  the  object  is  to  cause  sufficient  concentration 
in  the  brain  without  involving  the  heart  and  resjjiration. 

The  concentration  of  a  drug  in  a  cell  depends  in  tlu'  first  instance  on 


ELECTIVE  AFFINITY  OF  DRUGS  23 

the  concentration  in  which  it  is  present  in  the  surronndinj;-  fluids,  for 
the  passable  into  the  cell  appears  to  be  a  simple  difi'usion  wJiicli  folh)\vs 
tlie  hiw  of  mass  action.  And  in  many  cases  there  seems  to  l)e  no  greater 
concentration  than  is  in  accord  with  dilVusion,  the  drug  being  present 
in  the  cell  in  the  same  concentration  as  in  the  fluid;  for  example, 
carbolic  acid  is  not  actively  taken  up  by  bacteria.  In  other  instances 
the  drug  is  deposited  in  the  cell  in  some  form  of  combination,  chemical 
or  physical,  and  the  dift'usion  continues  until  the  cell  may  contain  the 
whole  of  the  drug  and  the  surrounding  fluid  is  free  from  it;  an  instance 
of  this  is  presented  by  the  accumulation  of  mercury  in  bacteria.  As 
the  drug  is  accumulated  in  the  cell  it  may  finally  reach  a  strength  that 
provokes  reaction,  but  in  some  instances  the  drug  accumulates  in  large 
amount  without  interfering  with  the  functions  of  the  cell. 

The  concentration  of  a  drug  in  the  tissues  depends  primarily  on  the 
dose  given,  but  this  is  modified  by  the  rate  of  absorption  and  the  rate 
at  which  the  body  frees  itself  from  the  drug  by  excreting  it,  or  changing 
it  into  harmless  forms.  Small  divided  doses  of  a  remedy  may  thus 
never  cause  the  same  symptoms  as  the  administration  of  the  same 
amount  undivided.  The  most  striking  instance  of  this  is  offered  in 
anaesthesia,  for  during  an  operation  of  an  hour's  duration  much  larger 
amounts  of  chloroform  or  ether  are  taken  into  the  tissues  than  would 
be  fatal  if  inhaled  more  rapidly;  the  fatal  concentration  is  not  reached 
because  while  absorption  is  going  on  throughout  the  stage  of  ansesthesia, 
excretion  is  proceeding  equally  rapidly. 

ELECTIVE  AFFINITY  OF  DRUGS.     PROTOPLASM  POISONS. 

Most  drugs  have  an  elective  affinity  for  certain  definite  tissues. 
Thus,  some  attack  the  heart  only,  others  the  central  nervous  system 
and  others  the  terminations  of  the  motor  nerves  in  muscle.  Among 
the  cardiac  poisons  again,  some  act  on  the  ventricle,  others  on  the 
auricle,  and  among  the  poisons  of  the  central  nervous  system,  some  act 
primarily  on  the  cortex,  others  on  the  medulla  oblongata  and  others 
on  the  spinal  cord.  This  elective  affinity  is  not  merely  a  question  of 
degree,  as  is  sometimes  stated,  for  a  drug  which  has  a  powerful  action 
on  the  brain  may  have  no  eft'ect  on  the  heart  except  when  administered 
in  such  quantities  as  alter  the  physical  characters  of  the  blood.  A 
drug  may  even  alter  different  structures  in  diametrically  opposite 
directions.  Thus,  atropine  depresses  certain  nerve  terminations,  but 
stimulates  the  brain;  and  curara,  which  paralyzes  the  peripheral  ter- 
minations of  the  motor  nerves,  stimulates  the  spinal  cord.  In  some 
instances  the  immunity  of  a  cell  to  the  action  of  a  drug  may  perhaps 
be  explained  by  the  latter  failing  to  penetrate  into  its  interior,  but 
this  is  not  true  in  all  cases. 

The  fields  of  activity  of  diff'erent  drugs  vary  greatly  in  extent.  One 
may  comprise  only  the  terminations  of  the  secretory  fibres  in  the  sweat 
glands  (agaricin),  while  another,  which  affects  these  in  the  same  way, 
may  involve  many  other  terminations  in  its  action  (atropine).    Most 


24  INTRODUCTION 

poisons,  ho\vevcr,  wliilc  acting  on  a  certain  narrow  area  in  small  doses, 
extend  the  limits  of  their  activity  when  larger  (inantities  are  ingested. 
Thus,  a  poison  which  acts  in  small  doses  on  the  medulla  oblongata 
oidy,  may,  when  exhibited  in  larger  quantities,  involve  the  spinal  cord 
and  the  brain,  and  in  still  greater  concentration  may  affect  the  heart 
and  other  organs.  No  poison  is  known  that  acts  eciually  on  all  organs 
and  tissues,  but  those  which  have  a  wide  field  of  operation  are  often 
known  as  protoplasm  poisons.  These  paralyze  any  form  of  living 
matter  when  they  are  brought  in  contact  with  it  in  sufficient  quantity, 
but  if  they  are  injected  into  tlie  l)lood  and  thus  distributed  equally 
throughout  the  body,  they  invariably  select  some  special  organ  as  the 
chief  seat  of  their  activity.  This  is  exactly  parallel  to  the  behavior 
of  chemical  agents  in  the  laboratory.  For  example,  acetate  of  lead 
added  to  a  solution  of  a  chloride,  or  of  a  sulphate,  precipitates  it,  but 
added  to  a  mixture  of  the  two,  throws  down  more  of  the  sulphate 
than  of  the  chloride.  Nitrate  of  silver,  on  the  other  hand,  precipitates 
the  chloride  only.  Acetate  of  lead  may  be  compared  to  the  proto- 
plasm poisons,  nitrate  of  silver  to  those  with  a  less  extensive  field  of 
action.  As  protoplasm  poisons  affect  a  large  number  of  different 
forms  of  living  matter,  it  follows  that  they  alter  the  nutrition  rather 
than  specialized  functions.  Many  of  them  cause  irritation;  others  are 
used  to  destroy  or  retard  the  growth  of  microbes  and  are  known  as 
disinfectants  or  antiseptics. 

REMOTE,  LOCAL,  AND  GENERAL  ACTION. 

Drugs  change  directly  only  those  organs  and  tissues  with  which  they 
come  into  immediate  contact.  But  the  alteration  of  one  part  of  the 
organism  very  often  entails  that  of  another  to  which  the  drug  may  not 
have  access,  or  for  which  it  has  no  special  affinity,  because  impulses 
are  transmitted  through  the  nerves,  or  changes  are  induced  in  the  cir- 
culation and  nutrition.  Thus  irritation  of  the  skin  may  alter  the  rate 
of  the  pulse  by  imj)ressions  being  transmitted  by  the  cutaneous  nerves 
and  reflected  along  the  inhibitory  nerves  of  the  heart.  Similarly  a 
poison  that  weakens  the  heart  may  induce  disorder  of  the  respiration, 
from  the  circulation  being  deficient  in  the  medulla  oblongata;  and 
depression  of  the  brain  may  lessen  the  oxidation  in  the  muscles, 
because  it  leads  to  lessened  movements.  These  secondary  changes, 
which  are  not  due  to  the  direct  action  of  the  drugs  on  the  organs  con- 
cerned, are  known  as  remote  or  indirect  ell'ects. 

The  local  action  of  a  drug  is  that  induced  at  the  point  of  application 
before  it  enters  the  circulation,  the  (jeucral  or  systemic  action  is  that 
due  to  its  elective  affinity  for  certain  organs  to  which  it  is  carrieil  by 
the  blood.  The  local  effects  are  very  often  entirely  diiVerent  in  nature 
from  the  general  action,  for  a  drug  may  act  as  an  irritant  at  the  point 
of  application  and  as  a  depressant  to  the  l)rain  when  it  is  carried  to  it 
in  the  blood.  Local  edVcts  may  be  induced  wherever  the  drug  can  be 
appHed— in  the  skin,  the  alimentary  tract,  the  resjHratory  passages, 


SALT-ACTION  25 

and  the  other  mucous  membranes.  They  also  occur  in  the  subcu- 
taneous tissues  when  the  poison  is  injected  hypodermically,  and  in  any 
of  the  deeper  organs  and  tissues  which  can  be  readied  by  the  needle  of 
the  syringe.  Local  remedies  may  cause  irritation,  or  may  protect  the 
surface  from  irritation,  may  depress  the  sensory  end-organs  and  cause 
local  anaesthesia,  or  lessen  secretion,  or  alter  the  functions  at  the  point 
of  application  in  many  other  ways.  They  may  also  have  remote 
effects,  as  has  been  mentioned.  Many  drugs  have  only  a  local  action, 
because  they  are  not  absorbed,  are  absorbed  in  inactive  forms,  or  are 
excreted  or  deposited  as  rapidly  as  they  pass  into  the  circulation,  so 
that  enough  is  not  present  in  the  blood  at  any  one  time  to  induce 
general  effects.  On  tlie  other  hand,  many  powerful  poisons  have  little 
or  no  effect  at  the  point  of  application,  but  possess  an  elective  affinity 
only  for  some  organ  to  which  they  are  carried  by  the  circulation. 


SALT-ACTION.i 

Salt-action  is  the  term  applied  to  a  series  of  reactions  which  occur 
from  the  physical  effects  of  solutions,  and  which  are  analogous  to 
changes  in  dead  tissues  and  are  explained  in  the  same  way.  Salt-action 
is  elicited  by  any  substance  which  can  circulate  in  the  body  in  sufficient 
concentration;  it  is  oftenest  seen  under  the  salts  of  the  alkalies,  but 
is  equally  elicited  by  sugar,  urea,  and  other  harmlesss  organic  substances; 
on  the  other  hand  the  more  powerful  poisons  never  reach  the  concentra- 
tion in  the  tissues  which  is  necessary  to  ehcit  salt-action. 

Salt-action  depends  on  the  relative  ease  with  which  a  salt  and  the 
water  in  which  it  is  dissolved  diffuse  into  the  cells  with  which  they 
come  in  contact.  When  a  solution  of  salt  is  brought  in  contact  with 
one  containing  sugar,  the  salt  molecules  and  ions  rapidly  diffuse  into 
the  sugar  solution  and  the  sugar  molecules  into  the  salt  solution  until 
the  whole  becomes  homogeneous,  each  part  containing  the  same  amount 
of  sugar  and  salt.  In  the  same  way  if  a  living  cell  be  brought  into  a 
solution  of  sugar,  there  is  often  a  diffusion  in  both  directions,  the  sugar 
passing  into  the  cell  and  the  salts  of  the  cell  passing  into  the  solution 
until  the  fluid  within  and  without  the  cell  becomes  identical  in  com- 
position. If  much  sugar  diffuses  into  the  cell  this  may  disturb  the 
equilibrium,  and  changes  in  the  activity  of  the  cell  may  follow,  or  if 
the  salts  and  other  diffusible  bodies  in  the  cell  escape  in  large  quantities 
into  the  fluid,  this  may  again  change  the  life  processes  in  the  cell.  Marked 
reactions  may  thus  arise  from  changes  in  the  constituents  of  the  liquids 
surrounding  a  cell  even  though  these  constituents  are  comparatively 
inactive  themselves;  and  the  reduction  in  the  amount  of  a  constituent 
of  the  plasma  may  prove  as  harmful  as  its  presence  in  excess,  by  causing 
the  escape  of  essential  constituents  of  the  cell. 

1  A  more  detailed  account  of  the  salt-action  in  different  organs  will  be  given  in  the 
Chapter  on  Sodium  Chloride  and  Water,  to  which  the  reader  is  referred.  Here  only  the 
general  principles  are  dealt  with. 


26  INTRODUCTION 

Pure  water  diffiiscs  readily  into  all  cells  and  eauses  disturbance 
in  their  functions  from  reducin*,'  the  concentration  of  their  soluhle  con- 
stituents. And  some  solids  also  appear  to  diffuse  with  little  difhculty 
into  many  cells.  But  it  is  found  that  most  dissolved  substances  meet 
with  some  resistance  in  entering  cells,  and  that  different  tissues  also 
vary  in  this  relation,  one  set  of  cells  taking  up  many  salts  with  readiness, 
while  another  set  permits  the  passage  of  few  of  these  and  rejects  others. 
When  a  salt  can  penetrate  a  cell  readily,  the  w^ater  in  which  it  is  dis- 
solved also  finds  no  resistance  to  its  entry,  and  the  contents  of  the  cell 
are  thus  diluted  as  much  as  if  they  had  been  exposed  to  pure  water. 
On  the  other  hand,  if  a  salt  cannot  penetrate  into  a  cell,  it  holds  back 
a  certain  proportion  of  the  water  in  which  it  is  dissolved,  and  osmotic 
currents  are  set  up  between  the  soluble  bodies  and  water  in  the  interior 
of  the  cell  and  the  solution  outside  it.  If  the  latter  is  the  stronger  in 
osmotic  pressure  (hypertonic  solution),  the  water  of  the  cell  diffuses 
into  the  external  solution;  if  the  osmotic  pressure  of  the  cell  contents 
is  the  higher,  the  movement  of  the  water  is  toward  the  interior  and  the 
solution  is  said  to  be  hypotonic;  if  the  osmotic  pressure  in  the  cell 
contents  is  equal  to  that  of  the  solution  (isotonic  solution)  there  is  no 
movement  of  the  water  and  the  volume  of  the  cell  remains  unchanged. 
The  behavior  of  a  cell  and  the  surrounding  fluid  is  thus  of  the  same 
character  as  that  observed  between  the  fluids  on  the  two  sides  of  a 
membrane  in  the  physical  laboratory;  but  no  dead  membrane  is 
known  which  differs  so  much  in  its  behavior  to  various  salts  as  the 
living  cell,  and  the  behavior  of  fluids  and  salts  is  further  complicated 
by  the  fact  that  the  permeability  of  the  different  cells  varies  greatly. 

As  an  example  of  salt-action  the  reactions  of  the  red-blood  cells  may 
be  given:  water  penetrates  into  these  readily,  and  when  the  cells  are 
placed  in  distilled  water  it  passes  into  them  until  they  swell  up  and 
burst;  ammonium  cliJoride  penetrates  readily  also,  and  in  solutions  of 
this  salt  the  red  cells  behave  almost  as  if  they  were  placed  in  distilled 
water;  sodium  chloride  hardly  penetrates  these  cells,  and  when  they 
are  placed  in  a  solution  of  sodium  chloride  of  the  same  osmotic  pressure 
as  that  iti  the  interior  of  the  cell  (isotonic),  there  is  no  movement  of 
water  into  the  interior  since  the  water  of  the  solution  is  held  back  by 
the  sodium  chloride;  if  a  solution  of  lower  osmotic  pressure  (hypotonic) 
is  employed,  a  certain  amount  of  water  is  taken  up  from  it  by  the  cell, 
the  weaker  sodium  chloride  being  unable  to  compete  with  the  attraction 
of  the  stronger  solution  in  the  interior  of  the  cell.  On  the  other  hand 
if  a  solution  of  higher  osmotic  j)ressure  (hypertonic)  be  used,  it  with- 
draws fluid  from  the  cell,  which  shrinks,  because  the  salts  in  the  interior 
are  unable  to  retain  the  water  against  the  stronger  concentration 
outside.  The  behavior  of  the  epithelium  of  the  intestine  toward  these 
salts  offers  a  contrast  to  that  of  the  red-blood  cells,  for  the  chlorides 
of  sodium  and  of  anmionium  are  both  readily  absorbed  by  the  intestine; 
on  the  other  hand  the  sulphate  of  sodium  fails  to  penetrate  the  red  cells 
anfl  enters  the  intestinal  e|)ithelium  with  great  difticult.w 

.Soluble  salts  exist  in  the  bodv  mainh"  as  ions,  and  each  ion  cxiTts 


CONDITIONS  MODIFYING  THE  EFFECTS  OF  DRUGS  27 

the  same  osmotic  pressure  as  an  imdissociated  molecule.  And  cacli 
ion  possesses  an  in(le])eii(lent  pliarmacolouieal  action.  For  example, 
when  cyanide  of  potassium  is  given,  the  action  may  arise  from  eitlier  the 
potassium  or  the  cyanide  ion,  and  when  potassium  hydrate  is  ai)plie(l, 
the  effects  may  arise  from  either  the  K-ion  or  from  the  HO-ion.  In 
many  instances  one  ion  is  so  powerful  that  the  other  may  be  neglected; 
thus  when  potassium  cyanide  is  given,  the  cyanide  acts  in  such  minute 
quantities  compared  with  the  comparatively  inert  K-ion  that  the  latter 
is  never  present  in  sufficient  quantity  to  elicit  symptoms.  On  the  other 
hand  when  the  ions  are  more  equal  in  power  each  has  to  be  taken  into 
account  in  analyzing  the  action;  thus  when  magnesium  sulphate  is 
administered,  the  Mg-ion  and  the  S04-ion  each  bear  a  part  in  the  effects. 
Many  drugs  are  not  dissociated  in  the  tissues  and  act  only  as  mole- 
cules and  not  as  ions;  thus  C2H5HO  does  not  dissociate  the  HO-ion 
as  KHO  does,  and  none  of  the  characteristic  effects  of  this  ion  are 
elicited  by  the  former.  This  has  often  given  rise  to  confusion,  especially 
in  connection  with  organic  bromine  compounds.  The  bromide  ion  has  a 
valuable  action  which  follows  when  the  dissociable  bromides  are  given, 
but  no  such  effects  follow  from  such  bodies  as  CHBrs  because  these  do 
not  dissociate  the  Br-ion.  Compounds  which  dissociate  poisonous 
ions  are  thus  to  be  differentiated  from  others  in  which  the  same  con- 
stitutents  are  present  in  undissociable  combinations.  Another  example 
of  this  is  offered  by  the  toxicity  of  potassium  cyanide,  which  liberates 
the  CN-ion,  and  the  inactivity  of  potassium  ferrocyanide,  which  contains 
CN  but  does  not  dissociate  the  CN-ion  but  the  more  complex,  harmless 
ferrocyanide  ion. 

CONDITIONS  MODIFYING  THE  EFFECTS  OF  DRUGS. 

The  effects  of  drugs  on  the  living  organism  are  subject  to  some 
modifications  in  certain  individuals  and  under  some  conditions,  which 
it  is  of  importance  that  the  physician  should  recognize,  as  the  dose 
has  to  be  altered  when  they  are  present.  One  of  these  is  the  Size  and 
Weight.  If  the  same  amount  of  a  poison  be  distributed  through  the 
tissues  of  a  large  individual  as  of  a  small  one,  the  concentration  is  lower 
in  the  organs  of  the  former  and  less  effect  is  therefore  observed.  This 
has  been  ascertained  chiefly  in  animal  experiment,  in  which  the  effects 
of  drugs  can  be  estimated  much  more  exactly  than  in  man,  but  it 
undoubtedly  holds  good  for  human  beings  also.  Very  large  indi- 
viduals, then,  require  a  somewhat  larger  dose  than  ordinary  persons, 
while  in  treating  individuals  of  small  stature,  the  dose  has  to  be 
reduced. 

The  Age  of  the  patient  has  also  to  be  taken  into  account  in  prescrib- 
ing. Children  ought  to  receive  much  smaller  doses  than  adults.  The 
more  powerful  action  of  drugs  in  children  is  due  in  part  to  their 
smaller  size,  in  part  to  the  more  active  growth  of  certain  tissues  and 
to  the  less  complete  development  of  others,  such  as  the  central  nervous 
system.     The  dose  for  a  child  is  generally  calculated  according  to 


28  INTRODUCTION 

Young's  formula,  in  wliicli  a  fraction  o})tained  by  dividing  the  age  by 
the  age  +  12,  is  taken  as  tlie  proportion  of  the  achilt  dose  required. 
Thus,  for  a  child  of  four  years,  the  dose  would  be  (^  +  12")  *  "^  ^^^^ 
adult  dose,  for  one  of  one  year  (^  +12")  ts  of  th^  adult  dose. 

Neither  Young's  formula  nor  any  of  the  others  which  have  been 
devised  in  its  stead  is  to  be  regarded  as  more  than  a  very  general 
approximation,  to  which  there  are  many  exceptions.  For  example, 
the  narcotics,  particularly  opium  and  its  preparations,  must  be  given 
during  the  first  year  of  life  in  much  smaller  quantities  than  are  indicated 
by  Young's  rule,  while  alcohol  may  be  administered  in  comparatively 
large  doses. 

The  usual  dose  advised  has  to  be  modified  for  children  then,  and 
may  be  taken  as  that  suitable  from  20-60  years.  After  this  age  is 
passed,  it  is  again  reduced  somewhat,  so  that  from  70-80  about  f  of 
the  adult  dose  is  advised,  and  after  85  it  may  be  reduced  to  \.  There 
are  exceptions  to  this  rule  also,  large  doses  of  the  purgatives,  for 
example,  being  often  necessary  in  old  people. 

Sex. — Women  generally  require  somewhat  smaller  doses  than  men, 
because  of  their  smaller  size,  and,  it  is  often  stated,  because  their  tissues 
react  more  strongly  to  some  drugs,  though  this  has  not  yet  been  satis- 
factorily established. 

Temporary  conditions  also  influence  the  activity  of  drugs.  Thus, 
after  a  meal,  a  poison  is  absorbed  more  slowly  from  the  stomach  than 
when  it  is  taken  fasting,  and  any  local  irritant  action  is  also  less 
marked,  because  the  drug  is  diluted  b}'  the  contents  of  the  stomach. 
Irritation  of  the  stomach  and  intestine  may  also  modify  the  effects  of 
drugs;  thus  in  some  forms  of  dyspepsia  the  absorption  is  slower  than 
usual  and  little  effect  may  be  induced  by  the  ordinary  dose,  while  irri- 
tant drugs  naturally  cause  more  disturbance  of  the  digestion  in  these 
cases.  Vomiting  and  diarrhoea,  of  course,  tend  to  lessen  the  action  of 
drugs  by  removing  them  rapidly  from  the  alimentary  canal. 

During  -pregnancy,  purgatives  have  to  be  used  with  great  care, 
because  they  induce  congestion  of  the  pelvis,  and  may  lead  to  abortion. 
Drugs  acting  on  the  uterus,  or  inducing  a  marked  fall  of  blood  pres- 
sure, are  to  be  avoided  because  the  former  may  cause  the  evacuation  of 
the  uterine  contents,  while  the  latter  may  lead  to  asphyxia  of  the  fa>tus. 
]\rany  drugs  pass  from  the  mother  to  the  child,  and  this  is  to  be  borne 
in  mind,  as  quantities  which  are  insufficient  to  poison  the  former  may 
have  more  serious  elfects  on  the  latter.  During  lactation,  it  is  impor- 
tant to  remember  that  active  bodies  may  be  excreted  in  the  milk,  and 
may  either  act  on  the  child  or  render  the  milk  distasteful  to  it.  In 
men.slniation,  [)urgatives  are  to  be  avoided,  as  they  tend  to  increase 
the  flow,  and  all  very  active  drugs  are  to  be  used  with  care  or  aban- 
doned tenii)()rarily. 

The  Time  of  Administration  has  also  some  inlliuiice  on  the  effects  of 
drugs.  The  body  is  generally  more  resistant  in  tlu>  morning  than  in 
the  evening,  especially  in  the  case  of  narcotic  tlrugs;  thus  a  dose  of  a 


CONDITIONS  MODIFYING  THE  EFFECTS  OP  DRUGS  29 

soporific  which  may  have  Httle  or  no  effect  in  the  early  hours,  induces 
sound  sleep  when  given  in  the  evening,  because  the  brain  is  already 
fatigued  and  depressed. 

Idiosjmcrasy  is  used  to  denote  an  unusual  effect  for  which  no  expla- 
nation can  be  found.  Some  persons  react  more  readily  than  usual  to 
the  ordinary  dose,  while  in  other  instances,  a  much  larger  quantity  can 
be  taken  without  any  effect.  Others,  again,  show  symptoms  which 
are  entirely  different  from,  and  which  may,  in  fact,  be  diametrically 
opposed  to  those  ordinarily  observed.  These  idiosyncrasies  are  nat- 
urally more  frequently  seen  and  are  better  known,  when  they  arise 
from  widely  used  drugs.  Thus  the  modern  antipyretics  have  so  often 
induced  abnormal  symptoms  that  these  are  well  known,  but  it  is  not 
improbable  that  if  other  drugs  had  been  used,  or  rather  abused,  to  the 
same  extent,  they  would  be  found  to  induce  unusual  reactions  in  an 
equally  large  number  of  individuals.  An  idiosyncrasy,  as  has  been 
said,  cannot  be  explained  in  the  present  state  of  knowledge,  but  some 
conditions  which  have  been  termed  idiosyncrasies  are  probably  due  to 
abnormally  rapid,  or  to  retarded  absorption  or  excretion.  Idiosyn- 
crasies are  not  confined  to  human  beings,  for  not  infrequently  one 
animal  reacts  quite  differently  from  others  of  the  same  species. 

As  has  been  mentioned,  one  form  of  idiosyncrasy  consists  in  the 
failure  of  the  individual  to  react  to  the  ordinary  dose  of  a  drug.  This 
is  known  as  Tolerance,  and  this  particular  form  of  idiosyncrasy  may 
be  termed  congenital  tolerance.  Certain  species  of  animals  tolerate 
quantities  of  drugs  which  would  be  fatal  to  others  of  the  same  size. 
In  fact,  so  frequently  is  this  the  case  that  it  is  impossible  to  determine 
the  fatal  dose  of  any  drug  on  an  animal  from  experiments  performed 
upon  others  of  a  different  species,  even  though  it  be  nearly  related. 
One  of  the  most  remarkable  examples  of  this  form  of  tolerance  is  met 
with  in  the  hedgehog,  which  resists  large  doses  of  many  very  active 
poisons.  Another  well-known  example  is  the  tolerance  of  the  rabbit 
of  large  quantities  of  atropine. 

A  form  of  tolerance  which  is  a  matter  of  everyday  observation  is  that 
induced  by  the  prolonged  use  of  a  drug,  which  has  been  called  acquired 
tolerance,  or  mithridatism,  from  the  belief  that  Mithridates  protected 
himself  in  this  way  from  the  danger  of  poisoning.  The  most  familiar 
example  of  this  form  of  tolerance  is  that  acquired  for  tobacco  (nico- 
tine); the  first  cigar  often  induces  violent  poisoning,  but  if  a  habit 
be  formed,  considerable  amounts  of  nicotine  may  be  absorbed  without 
apparent  harm,  because  the  tissues  become  accustomed  to  the  presence 
of  small  quantities  of  nicotine,  and  thus  fail  to  react  to  it.  Nicotine, 
in  fact,  becomes  a  normal  constituent  of  the  tissues.  This  tolerance 
is  entirely  different  from  the  immunity  induced  by  toxins  (see  Toxins), 
and  it  is  desirable  that  the  two  terms  should  be  kept  distinct. 

Very  often  while  tolerance  for  a  poison  is  established  in  certain  tissues, 
others  suffer  from  the  prolonged  use  of  excessive  quantities;  for  example, 
although  the  seasoned  smoker  does  not  suffer  from  the  nausea  and 
vomiting  which  followed  his  first  essay,  other  organs  may  in  course  of 


30  INTRODUCTION 

time  become  involved,  such  as  the  heart  or  the  eye.  It  is  to  be  noted 
that  tolerance  is  soon  lost  if  the  drug  be  discontinued  for  some  time. 
This  is  of  great  importance  in  cases  of  opium-eating,  for  a  person  who 
has  taken  opium  for  a  long  time  acquires  a  tolerance  for  the  drug,  so 
that  sometimes  enormous  quantities  are  required  in  order  to  induce  the 
ordinary  efl'ects;  but  if  the  habit  be  discontinued  for  some  time,  the 
tolerance  is  lost,  and  a  dose  which  would  formerly  have  had  little  efi'ect 
may  now  induce  dangerous  poisoning.  The  prolonged  use  of  one  drug 
may  establish  tolerance  for  others  of  the  same  class.  Thus  chronic 
drunkards  are  not  influenced  by  large  quantities  of  alcohol,  and  are 
also  more  resistant  to  the  action  of  chloroform  than  ordinary  persons, 
this  being  due  to  the  fact  that  chloroform  and  alcohol  act  on  the  same 
nerve  cells  in  the  same  direction,  and  proba})ly  induce  the  same  changes 
in  the  protoplasm. 

In  some  instances  when  tolerance  is  established  for  a  drug,  it  is 
found  that  the  tissues  destroy  more  of  it  than  previously  (morphine  and 
alcohol),  or  excrete  it  more  rapidly,  as  is  said  to  occur  under  atropine 
in  some  animals,  or  absorb  it  less  readily  (arsenic).  The  drug  thus 
never  reaches  the  same  concentration  in  the  tissues  and  the  absence 
of  action  is  thus  partly  explained.  In  addition  to  this,  however,  the 
organs  normally  affected  become  less  susceptible  to  the  drug;  for 
though  in  morphine  tolerance  much  more  is  destroyed  than  in  normal 
persons,  enough  remains  in  the  blood  to  cause  deep  narcosis  in  ordinary 
persons,  yet  no  symptoms  are  induced  in  the  patient. 

The  Cumulative  Effect  of  drugs  is  another  phenomenon  caused  by 
their  continued  ingestion.  Small  doses  of  certain  drugs  taken  repeat- 
edly for  some  time  eventually  cause  symptoms  which  are  much  more 
marked  than  those  that  follow  the  first  dose.  In  many  instances 
this  seems  due  to  the  accumulation  of  considerable  quantities  in  the 
tissues.  The  absorption  may  be  more  rapid  than  the  excretion,  and 
each  new  dose  thus  adds  to  the  total  quantity  in  the  blood  and  organs 
more  than  is  lost  in  the  same  time  by  excretion.  The  classical  example 
of  cumulative  action  is  that  of  digitalis,  but  it  is  much  more  frequently 
induced  by  such  drugs  as  mercury,  arsenic,  or  the  iodides,  for  the 
so-called  chronic  poisoning  induced  by  these  is  really  an  example 
of  cumulative  action.  Another  form  of  cumulation  is  said  by  Straub 
to  occur  in  chronic  lead  poisoning;  here  the  symptoms  appear  to  arise 
not  from  the  poison  collecting  in  the  tissues  until  it  reaches  an  efficient 
concentration,  but  from  the  cumuhitive  ciVect  of  continually  rci)eated 
injuries  from  the  presence  of  lead,  though  these  injuries  are  individually 
too  slight  to  be  noted.  ( "umulative  action  may  occur  along  with 
tolerance,  as  has  been  stated.  Thus  the  tolerance  of  certain  tissues  for 
nicotine  does  not  protect  others  from  the  eiVects  of  the  abuse  of  tobacco. 

Synergists.  Tli(>  i^rcsence  of  another  drug  having  the  same  efl'ects 
in  the  body  often  increases  the  action  of  a  remedy  to  an  unexpected 
extent.  This  is  the  ground  for  the  ])rescription  of  several  remedies 
acting  in  the  same  way.'     I'^or  i-\aniple,  several  jnirgatives  prescribed 

'  Tliu  less  important  oucs  arc  soinetimca  termed  adjuvants. 


CONDITIONS  MODIFYING  THE  EFFECTS  OF  DRUGS  31 

together  often  act  more  efficiently  than  any  one  given  in  quantity 
equal  to  all  of  them.  It  is  quite  impossible  to  explain  this  except 
by  assuming  that,  although  all  are  alike  in  their  chief  features,  they 
differ  in  the  details  of  their  reactions,  so  that  parts  of  the  alimentary 
canal  which  might  escape  one  are  affected  by  another,  and  the  mixture 
thus  acts  more  universally  than  any  one  of  the  components.  Other 
examples  of  synergism  are  offered  by  the  narcotics,  for  it  has  been 
shown  that  a  mixture  of  morphine  and  chloral,  for  example,  is  more 
efficient  than  either  administered  alone  in  larger  dose.  Another  recent 
example  is  oflFered  by  the  use  of  mercury  and  arsenical  compounds  in 
syphilis,  which  reacts  better  than  when  either  of  these  is  used  alone. 

On  the  other  hand,  a  drug  may  fail  to  elicit  any  symptoms  if  an 
antagonistic  substance  be  present  in  the  body.  Thus  in  cases  where 
a  powerful  nervous  depressant,  such  as  chloroform,  has  been  inhaled, 
strychnine  may  have  little  or  no  effect  on  the  spinal  cord  in  doses 
which  would  normally  increase  the  reflexes  to  a  marked  extent.  In 
the  same  way,  if  the  terminations  of  the  inhibitory  fibres  of  the  heart 
are  paralyzed  by  atropine,  a  poison  which  normally  slows  the  heart 
by  stimulating  these  terminations  will  have  no  such  effect  except  in 
very  much  larger  doses. 

Hunt  has  recently  discovered  a  series  of  relations  between  drugs, 
which  do  not  seem  to  fall  into  either  of  these  categories.  Thus  the 
administration  of  alcohol  renders  animals  more  susceptible  to  the 
action  of  acetonitrile,  and  thyroid  feeding  has  the  same  result  in  rats, 
while  it  increases  the  resistance  to  acetonitrile  in  mice. 

Similar  modifications  of  the  eftects  of  drugs  may  be  induced  by 
poisons  formed  by  pathological  changes  in  the  tissues,  or  by  an  unusual 
state  of  irritation  or  of  depression  of  the  tissues  themselves.  For 
example,  in  hot  weather  and  in  tropical  climates,  purgatives  are  found 
much  more  eflScient  than  in  colder  climates,  either  because  there  is 
some  poison  which  acts  along  with  the  purgative,  or  because  the 
mucous  membrane  is  more  irritable  than  usual.  That  some  such 
factor  is  present  in  these  conditions  is  shown  by  the  frequent  occur- 
rence of  diarrhoea  without  the  use  of  drugs.  Similarly  when  an  antago- 
nistic poison  is  formed  in  the  tissues  in  the  course  of  a  disease,  a  drug 
may  have  little  or  no  effect. 

Pathological  conditions  very  often  modify  the  effects  of  drugs  to  a 
very  considerable  extent,  and  in  a  way  which  cannot  be  explained  at 
present.  For  example,  the  antipyretics  reduce  the  temperature  in 
fever,  but  have  no  effect  on  it  in  health;  the  bromides  lessen  the  con- 
vulsions in  epilepsy,  but  have  much  less  effect  in  depressing  the  brain 
in  normal  persons.  The  question  may  therefore  be  raised  whether 
the  examinatin  of  the  effects  of  drugs  in  normal  animals  is  of  much 
value  in  indicating  their  therapeutic  action.  But  in  reply  it  may  be 
said  that  in  a  large  number  of  instances  drugs  are  given,  not  in  order 
to  act  upon  the  diseased  tissues,  but  upon  healthy  ones.  The  object 
of  the  therapeutist  is  very  generally  not  to  restore  the  diseased  tissue 
but  to  relieve  it  from  work,  and  to  allow  it  rest  so  as  to  promote  its 


32  INTRODUCTION 

restoration  by  nature.  For  instance,  in  diseases  of  the  cardiac  valves, 
drugs  are  given,  not  with  the  object  of  restoring  their  integrity,  but  to 
act  upon  the  liealthy  heart  muscle,  and  to  ob\iate  the  disturbance  of 
the  circulation  which  is  caused  by  the  destruction  of  the  valves.  In 
inflammation  of  the  kidneys,  the  physician  seldom  attempts  to  reduce 
the  inflammation  by  the  action  of  drugs  on  the  cells  involved,  but 
confines  his  attention  to  removing  by  other  channels  the  ])roducts  of 
tissue  waste,  which  would  normally  be  excreted  by  the  kidney.  So 
that  in  most  instances  drugs  are  given  to  act  on  normal  tissues,  or  on 
tissues  which  are  so  little  affected  by  disease  that  they  react  to  remedies 
in  the  same  way  as  the  normal.  In  other  cases  the  action  of  drugs 
on  diseased  tissues  or  on  the  causes  of  disease  may  be  investigated  by 
inducing  the  disease  in  animals,  as  has  been  done  very  largely  in  recent 
vears  in  various  infectious  diseases.^ 


METHODS  OF  ADMINISTRATION. 

The  effect  of  a  remedy  is  often  determined  very  largely  b}'  the 
method  in  which  it  is  administered.  As  regards  the  local  action,  this 
is  suflficiently  obvious,  for  an  irritant  applied  to  the  skin  could  scarcely 
be  expected  to  cause  the  same  symptoms  as  if  it  were  applied  to  the 
stomach  and  intestine.  But  the  same  holds  true  for  the  general  action 
in  most  instances,  because  some  tissues  and  organs  absorb  much  more 
rapidly  than  others,  and  a  larger  quantity  of  the  drug  therefore  passes 
through  them  into  the  blood  in  a  given  time.  Thus,  if  a  poison  which 
is  absorbed  slowly,  be  rapidly  excreted,  so  little  of  it  may  exist  in  the 
l)lood  and  tissues  at  any  given  time  that  no  effects  are  induced,  while 
if  it  be  rapidly  absorbed  by  some  other  method  of  administration,  the 
same  dose  can  exert  some  action  before  it  is  excreted. 

Drugs  are  applied  for  their  Local  Action  to  the  skin,  to  the  mucous 
membranes  of  the  alimentary,  respiratory,  and  genito-urinary  tracts, 
and  to  the  conjunctiva  and  cornea.  Not  infrequently  they  are  injected 
by  means  of  tlie  hypodermic  needle  into  the  subcutaneous  tissues  for 
their  local  effects,  and  the  attempt  is  continually  being  renewed  to 
treat  even  the  deeper  tissues  and  organs  locally  by  the  injection  of 
remedies  into  them.  The  objects  of  local  medication  are  very  diverse, 
and  can  be  treated  of  only  in  connection  with  the  individual  drugs. 
The  methods  of  ai)plication  are  also  so  numerous  that  only  a  few  of  the 
chief  can  be  mentioned.  Drugs  intended  for  application  to  the  skin 
arc  often  formed  into  salves  or  ointments  (unguenta)  by  mixing  them 
with  oily  or  fatty  substances,  which  adhere  to  the  skin  and  do  not 
dry  uj),  and  which  in  addition  to  serving  as  a  means  of  applying  an 
active  substance,  i)rotect  the  surface  from  the  air  and  from  irritation. 
Other  preparations  for  application  to  the  skin,  such  as  the  plasters 
(emplastra),  resemble  tlie  ointments  in  their  general  cliaracters,  but 

'  Thia  method  of  inveatinaUon  luul  its  results  am  sometimes  known  as  chc mother ap rj , 
but  they  do  not  differ  in  esscntiaia  from  those  of  pharmacology. 


METHODS  OF  ADMINISTRATION  33 

also  give  mechanical  support  and  bind  surfaces  togethcF  from  their 
being  spread  on  paper  or  cloth,  which  thus  serves  as  a  flexible  splint. 
The  collodions  and  cerates  resemble  the  plasters,  the  oleates  the  oint- 
ments. In  addition  to  these  special  preparations,  drugs  may  be  applied 
to  the  skin  in  solutions,  or  as  powders,  or  solid  masses  may  be  used  to 
cauterize  it. 

The  methods  of  applying  drugs  to  the  alimentary  tract  and  to  the 
lungs  for  their  local  action  are  for  the  most  part  similar  to  those  used 
for  drugs  which  are  intended  to  be  absorbed.  The  mouth  and  throat 
may  be  washed  out  with  solutions,  which  are  gargled  (gargarismata), 
or  may  be  treated  with  powders,  or  lozenges  (trochisci),  which  are 
slowly  dissolved  and  thus  permit  of  a  more  prolonged  and  constant 
action  in  the  mouth  than  is  possible  if  the  drug  be  swallowed  imme- 
diately. The  nose  may  be  washed  out  with  solutions  of  active  drugs, 
or  powders  may  be  drawn  into  the  nostrils  as  snuffs;  the  latter  often 
cause  sneezing,  and  are  sometimes  known  as  sternutatories,  or  errhines. 
The  larynx  may  be  treated  locally  by  the  application  of  powders  or 
of  very  small  quantities  of  fluids  by  means  of  the  laryngoscopic  mirror 
and  probe.  Solutions  are  generally  used  for  application  to  the  con- 
junctiva, but  a  more  permanent  eiTect  can  often  be  obtained  from 
ointments,  lamellfe,  or  powders  which  are  less  liable  to  be  washed  away 
by  the  tears.  The  urethra,  vagina  and  uterus  are  treated  by  the 
injection  of  solutions,  or  by  ointments  and  powders.  Bougies,  which 
are  occasionally  advised,  are  formed  by  incorporating  an  active  drug 
in  some  substance  which  is  solid  at  ordinary  temperatures,  but  melts 
when  introduced  into  the  organ  and  allows  the  drug  to  come  into 
contact  with  the  surface.  The  rectum  may  similarly  be  treated  by  the 
injection  of  drugs  in  solution  or  suspension  (enemata),  or  by  the  use 
of  suppositories.  Drugs  are  not  infrequently  applied  by  the  rectum 
in  order  to  elicit  their  action  after  absorption,  but  much  oftener  for 
their  local  action  on  the  bowel.  Enemata  may  be  either  large  (a  pint 
or  more)  or  small  (2-5  c.c,  ^-1  fl.  dr.).  The  large  enemata  are  used 
either  to  wash  out  the  intestines,  and  may  then  contain  an  antiseptic 
or  astringent,  or  to  induce  peristalsis  and  evacuation  of  the  bowel, 
when  they  are  made  up  of  water  with  or  without  soap  or  other  slightly 
irritant  substances.  The  small  enemata  are  used  chiefly  to  induce 
evacuation,  and  contain  more  irritant  substances,  such  as  glycerin 
alone  or  along  with  some  more  active  body.  The  suppositories  are 
formed  of  cacao-butter,  which  is  solid  at  room  temperatures,  but  melts 
at  the  temperature  of  the  rectum. 

Drugs  whose  General  Action  is  to  be  elicited  after  their  absorption 
are  given  by  the  mouth,  except  when  some  special  character  in  them 
or  in  the  disease  renders  some  other  method  preferable.  They  may  be 
given  by  the  mouth  in  solution  in  water,  alcohol,  oils,  or  other  more 
or  less  indift'erent  bodies.  The  disagreeable  taste  of  many  remedies, 
however,  often  precludes  this  method,  and  these  may  be  ordered  in  the 
form  of  pills,  or  in  capsules,  which  are  formed  of  gelatin  or  similar 
substances  and  are  dissolved  in  the  stomach  and  intestines.  Very 
3 


34  INTRODUCTION 

often  the  disagreeable  taste  may  be  concealed  by  the  addition  of  sugar, 
or  of  some  strongly  tasting  but  agreeable  body,  such  as  a  volatile  oil. 
Insoluble  drugs  may  be  given  as  powders,  as  they  have  little  or  no 
taste.  Powders  are  also  used  as  a  means  of  administering  soluble 
drugs,  if  they  have  not  a  disagreeable  taste  and  have  no  marked  local 
action,  but  very  deliquescent  drugs  should  not  be  given  in  this  form. 
Insoluble  drugs  are  sometimes  ordered  in  suspension  in  mucilaginous 
fluids;  and  oils  which  are  distasteful  to  many  people,  may  be  given 
mixed  with  water  and  gums  (emulsions). 

The  rate  of  absorption  from  the  alimentary  canal  varies  greatly 
with  different  drugs  and  also  with  the  form  in  which  they  arc  adminis- 
tered. The  first  point  will  be  treated  of  in  connection  with  the  indi- 
vidual drugs.  As  regards  the  second,  it  may  be  stated  that  drugs  are 
more  rapidly  absorbed  when  they  are  swallowed  in  solution,  and  that 
when  much  inert  and  insoluble  matter  is  associated  with  them,  their 
absorption  is  much  retarded.  Thus,  common  salt  passes  more  rapidly 
into  the  blood  when  it  is  dissolved  before  being  taken  than  when  it  is 
swallowed  dry,  and  morphine  is  absorbed  much  more  quickly  when  it 
is  administered  pure  than  when,  as  in  opium,  it  is  mixed  with  a  mass 
of  gums  and  other  bodies.  This  fact  is  taken  advantage  of  in  practice 
by  giving  drugs  in  solution  when  rapid  absorption  is  desirable,  and  by 
giving  less  pure  forms  when  the  local  action  on  the  stomach  and  bowel 
is  to  be  elicited.  The  more  concentrated  the  solution,  the  greater  is 
the  irritant  action  on  the  stomach,  and  thus  where  irritation  of  the 
stomach  is  desired,  either  the  solid  drug  or  a  strong  solution  is  given; 
but  as  a  general  rule  the  local  action  on  the  stomach  is  to  be  avoided, 
and  drugs  are  therefore  ordered  in  as  dilute  solution  as  is  possible 
without  increasing  the  bulk  to  too  great  an  extent.  It  is  to  be  noted 
that  drugs  which  are  insoluble  in  the  test-tube  may  be  rendered  soluble 
by  the  action  of  the  gastric  and  intestinal  juices,  while  many  which 
are  given  in  solution,  are  precipitated  by  the  proteins  in  the  stomach. 

The  great  mass  of  drugs  absorbed  from  the  stomach  and  intestine 
is  carried  to  the  liver  before  reaching  the  general  circulation,  and  this 
is  of  great  importance  in  determining  their  effects  in  the  body,  as 
some  of  them  are  retained  in  that  organ,  and  are  either  entirely 
destroyed  or  escape  so  slowly  that  they  have  no  perceptible  effect. 

Another  important  method  of  administering  drugs  for  their  general 
action  and  also  for  their  local  effects  is  by  inhalation  into  iJw  lungs. 
Only  volatile  drugs  can  be  used  thus  for  their  general  action,  "^riiey 
are  absorbed  very  rapidly  owing  to  the  extensive  surface  to  which  they 
are  applied,  and  also  because  volatile  substances  penetrate  the  tissues 
more  readily  than  others.  The  best  examples  of  inhalation  are  offered 
by  the  general  anesthetics,  chloroform  and  ether.  Most  substances 
absorbed  by  the  lungs  are  also  ex('ret(>d  by  them,  and  this  leads  to  an 
important  j)racti(al  point  in  regard  to  the  ana'stlietics.  For  the  passage 
of  gases  or  vapors  through  the  lining  epithelium  of  the  alveoli  depends 
in  most  instances  upon  their  partial  |)ressure,  that  is,  upon  their  con- 
centration in  the  air  and  blood  resj)ectively.    Accordingly,  when  the  air 


METHODS  OF  ADMINISTRATION  35 

contains  more  chloroform  vapor  than  the  blood,  the  anaesthetic  passes 
into  the  bk)od,  but  as  soon  as  the  condition  is  reversed,  and  the  blood 
contains  more  chloroform  than  the  air  of  the  alveoli,  it  commences  to 
pass  backward.  The  more  concentrated  the  vapor  inhaled,  the  more 
chloroform  is  contained  in  the  cubic  centimeter  of  blood,  and  the 
greater  is  the  action  on  the  nervous  centres  and  the  heart. 

Less  volatile  substances  are  sometimes  inhaled  into  the  lungs  for 
their  local  action,  and  even  non-volatile  bodies  suspended  in  a  spray 
of  vapor  may  be  thrown  into  the  respiratory  passages,  but  it  may  be 
questioned  whether  these  last  really  reach  the  alveoli  except  in  traces. 

Drugs  are  also  applied  to  the  skin  in  order  to  elicit  their  general 
action.  Volatile  bodies  are  certainly  absorbed  by  it,  although  much 
more  slowly  than  by  the  lungs  or  by  the  stomach  and  intestine.  Solu- 
tions in  water  of  non-volatile  drugs  are  not  absorbed  from  the  skin, 
but  solutions  of  certain  remedies  in  alcohol,  oils,  fats,  ether,  and  some 
other  substances  which  are  capable  of  dissolving  or  mixing  with  the 
fatty  covering  of  the  skin,  are  absorbed  fairly  rapidly  if  they  are 
rubbed  in  thoroughly.  This  method  of  application  (inunction)  has 
been  used  chiefly  for  the  absorption  of  mercury,  as  the  local  action  on 
the  stomach  and  bowel  is  thus  avoided.  (See  Mercury.)  Alkaloids 
do  not  appear  to  be  absorbed  by  the  skin  even  when  dissolved  in  oils 
or  alcohol. 

The  hypodermic  method  is  of  comparatively  recent  origin,  but  is 
being  more  widely  used  every  year.  In  it  drugs  are  injected  through 
a  fine  hollow  needle  into  the  subcutaneous,  or,  in  the  case  of  more 
irritant  substances,  into  the  muscular  tissue,  where  they  meet  with 
fewer  sensory  nerves.  Absorption  occurs  more  rapidly  than  when 
drugs  are  given  by  the  mouth,  the  local  action  on  the  alimentary 
canal  is  avoided,  and  the  physician  is  more  certain  that  the  whole 
of  the  remedy  is  effective,  provided  it  is  soluble  and  is  not  pre- 
cipitated at  the  point  of  injection.  At  the  same  time,  the  method 
has  certain  drawbacks,  the  chief  of  which  are  the  pain  of  the  injection 
and  the  danger  of  injecting  a  powerful  remedy  into  one  of  the  sub- 
cutaneous veins.  Hypodermic  injection  should  be  made  only  by 
the  physician  or  trained  attendant,  for  incalculable  injury  has  been 
done  by  entrusting  patients  with  the  syringe,  particularly  for  the 
injection  of  morphine  and  cocaine.  The  needle  and  syringe  ought  to 
be  disinfected,  and  the  substance  injected  should  be  aseptic,  and  this 
renders  the  method  inconvenient.  As  a  general  rule,  solutions  in 
water  or  in  dilute  alcohol  are  used  for  injection,  but  the  insoluble 
salts  of  mercury  have  also  been  injected,  suspended  in  oil  (see  Mercury). 
Irritant  drugs  are  to  be  avoided  as  far  as  possible,  as  they  cause  great 
pain,  swelling  and  sometimes  suppuration,  even  when  the  injection 
has  been  carried  out  aseptically.  Hypodermic  injection  is  used  very 
largely  to  elicit  the  general  action  of  a  remedy,  but  also  for  the  local 
effects,  as  when  cocaine  is  injected  in  order  to  produce  local  ancTsthesia. 
Solutions  of  inert  bodies  have  also  some  anaesthetic  action,  })robably 
owing  to  their  mechanical  action  on  the  sensory  nerve  fibres.     As 


3G  INTRODUCTION 

tlie  absorption  from  the  subcutaneous  tissues  is  so  much  more  rapid 
than  tliat  from  the  stomach  and  intestine,  when  the  drug  is  in  perfect 
solution,  the  dose  has  to  be  reduced.  As  a  general  rule,  about  one-half 
of  the  ordinary  amount  is  sufficient. 

Deeper  injections  are  sometimes  made  for  their  local  action  on  the 
organs.  Thus,  antiseptics  liave  been  injected  into  lung  cavities,  caustics 
into  tumors,  local  anaesthetics  into  the  spinal  canal,  and  direct  applica- 
tions have  been  made  to  the  nerves  in  sciatica  and  other  similar 
disorders. 

I ntravenous  injection  is  the  most  certain  method  of  bringing  drugs 
into  the  circulation  and  tissues,  and  is  at  the  same  time  the  most 
rapid.  It  is,  therefore,  very  largely  used  in  experiments  on  animals, 
and  in  recent  years  has  been  widely  practised  in  man  in  such  diseases 
as  syphilis  and  malaria,  in  which  it  is  desirable  to  induce  a  definite 
concentration  of  a  remedy  in  the  blood  rapidly.  Cardiac  and  circulatory 
stimulants,  such  as  strophanthin  and  adrenaline,  have  also  been  admin- 
istered in  this  way.  The  dose  must  be  very  much  smaller  than  that 
employed  by  the  mouth,  but  it  is  impossible  as  yet  to  state  exactly 
what  fraction  will  induce  the  same  effects. 

Drugs  are  occasionally  applied  by  the  rectum  for  their  general 
action,  as  has  been  mentioned.  The  local  effects  on  the  stomach  are 
avoided  by  this  method,  and  morphine  and  opium  are,  therefore,  not 
infrequently  administered  thus.  The  rate  of  absorption  from  the 
rectum  as  compared  with  that  from  the  stomach  and  bowel  is  still  a 
disputed  point,  and  some  physicians  recommend  that  the  dose  be 
reduced  to  three-fourths,  while  others  recommend  one  and  one-half 
times  that  given  by  the  mouth. 

Drugs  are  not  administered  by  the  other  mucous  membranes  for 
their  general  effects,  but  it  must  not  be  forgotten  that  symptoms  may 
arise  from  their  application  to  them  for  their  local  action.  Similarly, 
drugs  applied  as  dressings  to  loounds  or  abrasions  have  very  often 
given  rise  to  severe  or  fatal  poisoning  from  being  absorbed  into  the 
blood  and  tissues. 

THE  CHEMICAL  CHARACTERS  OF  DRUGS. 

Many  substances  which  induce  changes  in  the  living  organism  arc 
comparativel>'  simple  chemical  compoimds.  In  the  inorganic  materia 
nicdica  are  found  many  salts,  bases  and  acids,  and  a  few  uncombincd 
elements,  such  as  mercury  and  phosphorus,  while  organic  chemistry 
offers  hydrocarbons,  alcohols,  ethers,  phenols,  ketones,  aldehydes,  acids, 
and  many  other  compounds  which  recjuire  no  special  mention.  V>\\\ 
some  groups  of  substances  which  occur  widely  in  ])hints  re(|uire  some 
discussion  behirc  the  indi\idual  members  arc  taken  up  sexcrally. 

The  first  gr(iii|)  of  these  is  formed  by  tlu'  Alkaloids,  which  are  sub- 
stituted anuiHiuias,  and  ha\c  a  more  or  less  strongly  alkaline  reaction, 
so  that  tlie\'  are  often  known  as  the  vegetable  bases.  They  contain 
carbon,  hydrogen,  nitrogen,  and,  as  a  general  rule,  oxygen,  although 


THE  CHEMICAL  CHARACTERS  OF  DRUGS 


37 


some  of  them,  such  as  coniine,  are  devoid  of  it.  Like  ammonia,  they 
combine  witli  acids  readily  without  ehminating  hydrogen,  and  the 
salts  thus  formed  resemble  those  of  ammonia  in  many  respects,  among 
others  in  being  thrown  out  of  combination  by  the  fixed  alkalies.  Many 
vegetable  alkaloids  are  derived  from  pyridine,  quinoline  and  isoc|uino- 
line  by  the  addition  of  hydrogen,  and  generally  by  the  substitution 
of  one  or  more  of  the  hydrogen  atoms  by  side  chains  of  greater  or  less 
complexit3\ 


CH 


CH 


HC 


/        \ 


HC 


/ 


CH 


CH 


HC 


HC 


/ 


CH 


\ 


CH 


CH 


HC 


/ 


HC 


HC 


HC 


N 
Pyridine. 


\/C   \/ 
CH  N 

Quinoline. 


CH 


N 


C    \/ 
CH  CH 

Isoquinoline. 


But  others  appear  to  be  derivatives  of  the  pyrrol  and  oxazine  groups, 
while  in  others  the  nitrogen  is  attached  to  radicles  belonging  to  the 
methane  or  open-chain  series;  some  artificial  alkaloids  are  derivatives 
of  anihne. 


HC 


HC 


NH 

Pyrrol. 


CH 


CH 


HC 


HC 


CH 

/        \  C— NHs 

CO 

Hc/        \ 

CH 

Aniline. 

N 
Oxazine. 

CH 


CH 


Finally  the  purine  bodies  (see  Caffeine  group)  may  be  included 
although  they  are  only  feebly  basic. 

Some  of  the  vegetable  alkaloids  have  been  formed  synthetically  in 
the  laboratory,  and  the  constitution  of  some  of  the  others  is  perfectly 
well  known,  but  many  of  them  have  not  yet  been  isolated,  and  there 
are  probably  others  whose  existence  is  not  even  suspected.  These 
vegetable  alkaloids  occur  in  almost  all  parts  of  plants,  although  they 
are  found  in  greatest  abundance  in  the  seeds  and  roots.  The  same 
alkaloid  is  often  found  in  most  of  the  plants  of  a  genus,  or  it  may 
occur  in  one  or  two  species  of  a  genus  and  in  other  plants  which  are 
in  no  way  related.  Very  often  several  alkaloids  are  found  in  a  plant, 
and  these  may  differ  entirely  in  their  action  on  animals,  although  not 
infrequently  all  the  alkaloids  of  a  plant  resemble  each  other  in  their 
effects.  The  alkaloids  are  found  most  abundantly  in  dicotyledonous 
plants,  but  some  are  obtained  from  the  monocotyledons.  Muscarine, 
ergotoxine  and  other  bases  are  found  in  the  fungi,  and  quite  recently 
alkaloids  have  been  isolated  from  the  suprarenal  capsule  of  animals 
and  from  the  skin  of  the  salamander. 

The  alkaloids  are  very  often  only  slightly  soluble  in  water,  but 
form  salts  which  are  generally  more  soluble.    Many  of  the  bases  are 


38  INTRODUCTION 

dissolved  l)v  etluT,  cliloroforin  and  amyl  alcoliol,  wliilc  the  salts  are 
insoluble  in  these.  Both  bases  and  salts  are  f:;enerally  fairly  soluble 
in  alcohol.-  The  alkaloids  are  precipitated  from  solution  by  a  large 
number  of  reagents,  of  which  the  most  important  are  the  chlorides  of 
platinum  and  of  gold,  tannic  acid,  phosphotungstic  and  phospho- 
molybdic  acid,  the  double  iodides  of  potassium  and  mercury,  and  of 
potassium  and  cadmium,  and  iodine  held  in  solution  in  water  by 
potassic  iodide.  The  hydrates  and  carbonates  of  the  alkalies  and  the 
alkaline  earths  precipitate  the  alkaloids  from  solutions  of  the  salts  in 
water,  a  point  of  some  importance  in  prescribing  these  bodies. 

In  cases  of  poisoning  when  the  alkaloid  has  been  taken  by  the  mouth, 
it  may  be  precipitated  in  the  stomach  by  dilute  alkalies  or  better  by 
tannin  solutions.  The  poison  should  then  be  removed  by  inducing 
vomiting  or  by  washing  out  the  stomach  with  the  stomach  tube. 

Another  important  class  of  vegetable  poisons  is  formed  by  the 
Glucosides  (glycosides),  or  saccharides,  which  are  esters  (compound 
ethers)  composed  of  sugars  and  hydroxyl  substances,  and  which  liberate 
sugar  when  they  are  heated  with  acids,  or  sometimes  with  alkalies, 
or  when  certain  unorganized  ferments  act  on  them.  The  sugar  formed 
in  this  way  is  often  glucose,  but  not  invariably  so;  the  other  decom- 
position products  have  been  identified  only  in  a  few  instances.  Many 
of  the  glucosides  contain  only  carbon,  hydrogen  and  oxygen,  a  few  have 
nitrogen  in  addition,  and  one  or  two  sulphur.  In  some  instances  the 
remainder,  after  the  sugar  is  split  oflf,  is  an  alkaloid,  e.  g.,  solanidine. 
Glucosides  differ  greatly  in  their  solubility  in  water  and  alcohol;  com- 
paratively few  of  them  are  soluble  in  ether.  Some  of  the  glucosides 
are  powerful  poisons,  others  have  little  or  no  action. 

Resins,  an  ill-defined  group,  are  found  in  many  plants,  and  are  char- 
acterized by  their  smooth,  shining  fracture,  and  by  their  insolubility 
in  water  and  solubility  in  ether,  chloroform,  volatile  oils,  benzol  and, 
in  many  cases,  in  alcohol.  They  seem  to  be  formed  in  plants  by  the 
oxidation  of  volatile  oils,  and  are  often  acid  or  anhydride  in  character, 
while  others  are  apparently  alcohols  or  esters.  The  resins  are  almost 
invariably  comi)osed  of  several  diti'erent  substances  mixed  together. 
Many  of  the  resins  are  local  irritants,  and  some  are  poisonous  in  com- 
paratively small  quantity  from  the  powerful  action  they  exert  on  the 
intestine. 

Oleoresins  are  solutions  of  resins  in  etluTeal  oils,  which  lend  them 
a  characteristic  odor  and  taste. 

The  term  "Bulsain"  is  often  used  as  synonymous  with  oleoresin,  but 
most  writers  restrict  it  to  those  oleoresins  which  contain  benzoic  and 
cinnamic  acid  along  with  other  constituents.    (See  Benzoic  Acid.) 

Gum-resins  are  mixtures  of  resins  and  gums,  generally  containing 
some  volatile  oils.  They  are  insoluble  in  water,  but  the  resin  is  sus- 
pended in  it  by  the  gum.  On  the  other  hand,  the  resin  is  dissolved 
by  alcohol,  while  the  gum  remains  insoluble. 

Gums  are  am()r!)hous.  transj)arent  substances,  composed  of  carbo- 
livdratesof  the  formula  ('ollujOr,  and  are  thus  nearlv  related  to  cellulose 


PHARMACOPCEIAS  AND  PHARMACOPCEIAL  PREPARATIONS     89 

iuui  starch.  Some  of  thcin  are  soluble  in  water,  while  others  merely 
swell  to  a  jelly  in  it;  they  are  insoluble  in  jijcohol.  They  generally 
occur  in  i)lants  in  combination  with  calcium,  magnesium  or  potassium; 
they  have  no  poisonous  action,  but  form  a  protective  covering  for 
irritated  surfaces,  and  are  largely  used  to  suspend  in  water  substances 
which  are  insoluble  in  it,  such  as  resins  and  oils. 

Volatile  oils  occur  in  plants  in  large  numbers.     (See  page  57.) 
Fats,  oils,  sugars,  acids,  starch,  proteins,  coloring  matter,  ferments 
and  other  bodies  which  occur  in  plants,  and  are  contained  in  many  of 
the  preparations  used  in  therapeutics,  are  not  generally  possessed  of 
any  action  of  importance. 

THE   PHARMACOPffilAS   AND   PHARMACOPCEIAL   PREPARATIONS. 

Almost  all  governments  have  found  it  necessary  to  regulate  the 
preparation  of  drugs  used  in  therapeutics,  and  for  this  purpose  issue 
at  intervals  codes  of  instructions  defining  the  characters  of  the  drugs 
and  giving  the  exact  formulae  according  to  which  they  are  to  be  pre- 
pared for  use.  In'  the  United  States,  where  the  government  has  not 
undertaken  this  as  yet,  a  code  has  been  prepared  by  a  voluntary  asso- 
ciation of  physicians  and  pharmacists.  These  codes  are  known  as 
Pharmacopoeias,  and  some  differences  exist  between  those  of  different 
states,  although  the  most  important  drugs  are  found  in  all  of  them. 
All  the  drugs  used  in  therapeutics  are  not  found  in  the  pharmacopoeias, 
for  these  are  issued  only  at  intervals  of  several  years,  and  in  the  mean- 
time valuable  remedies  may  be  introduced.  The  official  definition  of 
therapeutic  substances  is  of  advantage  to  both  physician  and  pharma- 
cist, as  it  assures  the  former  that  the  drug  he  prescribes  will  have  a 
uniform  quality,  wherever  in  the  country  it  is  dispensed,  while  the 
pharmacist  is  saved  from  the  continual  preparation  of  remedies  in 
different  forms,  by  their  being  prescribed  in  one  recognized  strength. 

The  pharmacopoeias  contain  a  large  number  of  pure  substances  such 
as  salts,  acids,  bases,  alkaloids,  and  these  require  no  further  description. 
On  the  other  hand,  many  of  the  drugs  are  given  in  an  impure  form, 
either  because  the  active  principle  is  unknown,  or  because  its  isolation 
is  attended  with  difficulty  and  expense.  Thus  many  of  the  vegetable 
remedies  are  presented  in  the  pharmacopoeias  as  solutions  or  solids 
which  contain  not  only  the  active  principle  but  gums,  sugars,  coloring 
matter,  and  many  other  impurities.  These  are  provided  in  different 
forms  to  allow  of  variation  in  their  administration.  In  addition,  the 
pharmacopoeias  contain  a  number  of  official  prescriptions,  that  is, 
mixtures  of  active  substances  in  such  proportions  as  are  ordinarily  pre- 
scribed. These  are  generally  designated  by  the  addition  of  "compound" 
(compositus)  to  the  name  of  the  chief  ingredient.  Most  pharmaco- 
poeias continue  to  use  Latin  in  the  titles  of  the  drugs,  and  this  is  not 
due  to  mere  pedantry  or  conservatism,  as  is  often  stated.  For  the 
popular  name  of  a  drug  is  often  used  for  several  different  substances, 
while  the  Latin  name  in  a  prescription  indicates  that  drug  which  is 


40  INTRODUCTION 

known  by  the  term  in  the  pharmacopoeia.  In  the  same  way  it  is  found 
necessary  to  maintain  Latin  terms  in  botany  and  zoology  in  order  to 
define  accurately  the  species. 

Many  crude  or  unprepared  drugs  are  found  in  the  pharmacopoeias, 
such  as  leaves,  roots,  flowers,  or  even  whole  plants.  These  are  used 
chiefly  for  the  preparation  of  other  more  readily  applicable  remedies, 
but  are  sometimes  prescribed  as  powders  or  in  pills. 

The  following  preparations^  are  official: 

a.  Aqueous  Preparations. 

Aqum,  medicated  waters,  generally  contain  only  traces  of  some  volatile 
substance,  such  as  an  ethereal  oil  or  chloroform,  in  solution  in  water,  and 
tliese  are  used  in  prescriptions  as  more  agreeable  to  the  taste  and  smell  than 
pure  water  but  have  no  further  effect.  In  the  U.  S.  P.  the  solutions  of 
ammonia,  and  hydrogen  peroxide  are  also  included  under  aqua^,  but  these 
are  used  only  to  elicit  the  specific  effects  of  these  drugs  and  are  powerful  poisons. 
In  the  B.  P'  these  strong  solutions  are  included  in  the  liciuores. 

Liquores  (U.  S.  P.)  are  solutions  in  water  of  soluble  substances.  Many  of 
tliese  are  one  per  cent,  in  strength. 

Liquores  (B.  P.)  are  solutions  in  the  widest  sense,  in  water,  alcohol,  or  other 

fluids.  •     •  1  1  •  r 

Decocta,  or  decoctions,  are  impure  solutions  of  vegetable  principles,  which 
are  obtained  by  boiling  parts  of  plants  in  water. 

Infusa,  or  infusions,  are  solutions  obtained  by  soaking  parts  of  plants  in 
water,  which  may  be  hot  or  cold,  but  is  not  kept  boiling.  Infusions  and  de- 
coctions are  weak  preparations  and  decompose  rapidly  so  that  they  are  used 
only  when  recently  prepared. 

Mistura;,  or  mixtures,  are  generally  preparations  in  which  substances  in- 
soluble in  water  are  suspended  in  it  by  means  of  gums  or  similar  viscid  sub- 
stances.    But  some  of  them  contain  only  solulile  bodies. 

Emulsa  (U.  S.  P.),  emulsions,  are  formed  by  suspending  oils  in  water  by 
means  of  gums  or  other  viscid  bodies.  The  B.  P.  contaiiis  no  official  emul- 
sions, the  corresponding  preparations  being  known  as  misturce. 

Mucilagines,  mucilages,  are  solutions  in  water  of  gums,  starch,  and  similar 
bodies. 

Syrupi,  syrups,  arc  strong  solutions  of  sugar  in  water,  Avhich  may  be  used 
alone,  or  may  be  impregnated  with  more  active  bodies.  Similar  pr-eparations 
formed  with  honey  instead  of  syrup  (sometimes  known  as  jnelliki)  are  official, 
as  Mel  Rosa3  (U.  S.  P.),  Mel  Boracis  (B.  P.). 

Lutiones  (B.  P.),  lotions,  or  washes.  This  term  is  used  to  designate  two 
preparations  of  mercury,  the  black  and  yellow  wash. 

b.  Alcoholic  Preparatio7is. 

Spiritus,  spirits,  are  solutions  of  volatile  bodies  in  alcohol,  and  often  owe 
their  chief  action  to  the  solvent  and  not  to  the  drug  contained  in  it. 

Elixiria  (U.  8.  P.),  elixirs,  dilTcr  from  spirits  cliicfly  in  containing  sugars, 
which  are  added  in  ortler  to  improve  their  taste. 

Tinctunv,  tinctures,  are  solutions  in  alcohol  of  medicinal  substances,  which 
are  generally  formed  by  .soaking  parts  of  plants  in  it.  They  contain  both 
volatile  aiuf  non-volatile  ingredients,  but  the  latter  arc  generally  the  more 
inii)ortaiit. 

1  The  .student  is  advised  to  omit  the  following  list  for  the  present,  and  to  refer  to  it 
only  as  he  takes  np  the  preparations  of  the  individual  druns.  Most  of  these  preparations 
are  found  in  both  phannacopcjuiaa.  Those  which  occur  only  in  the  British  arc  indicated 
by  H.  P.,  while  those  which  arc  confined  to  the  United  States  .are  marked  U.  S.  P. 


PHARMACOPCEIAS  AND  PHARMACOP(EIAL  PREPARATIONS     41 

Fluidextrada  (U.  S.  P.),  Extrada  Liquida  (B.  P.),  fluid  extracts,  are  j^rc- 
pared  from  plants  by  forming  solutions  in  water  or  more  frequently  in  alcohol, 
and  evaporating  them  until  the  solutions  contain  as  many  cubic  centimeters 
as  the  original  crude  drugs  weighed  in  granunes;  that  is,  the  volume  of  the 
fluid  extract  corresponds  to  the  weight  of  the  crude  drug.  When  the  active 
principle  is  assaj^ed,  however,  the  liquid  extract  is  diluted  to  contain  a  definite 
amount  of  it,  and  without  reference  to  the  quantity  of  the  crude  drug  used. 

The  tinctures  and  fluid  extracts  are  the  most  commonly  used  liquid  prepa- 
rations, and  most  of  the  important  drugs  are  prepared  in  one  or  both  of 
these  forms. 

c.  Other  Fluid  Preparations. 

Glycerita  (U.  S.  P.)  or  Glycerina  (B.  P.)  are  solutions  of  medicinal  substances 
in  glycerin. 

Collodia,  collodions,  are  solutions  of  medicinal  substances  in  collodion. 

Aceta,  or  medicated  vinegars,  are  solutions  of  medicinal  substances  in  vine- 
gar or  acetic  acid. 

Linimenta,  liniments,  embrocations,  are  preparations  in  which  active  rem- 
edies are  dissolved  or  suspended  in  dilute  alcohol,  oils,  or  water.  They  generally 
contain  an  oil  or  soap  and  are  intended  to  be  appUed  to  the  skin. 

d.  Solid  and  Semi-Solid  Preparations. 

Extrada,  extracts,  are  formed  from  solutions  such  as  tinctures,  decoctions, 
or  infusions  by  evaporation,  which  is  continued  until  there  remains  a  solid 
mass.  The  extracts  thus  contain  all  the  substances  which  are  taken  up  by 
the  solvent,  except  those  which  are  driven  off  or  decomposed  at  the  tempera- 
ture at  which  evaporation  is  carried  on. 

Pilulce,  pills,  are  globular  masses  of  small  size,  such  as  admits  of  their  being 
easily  swallowed.  They  are  formed  from  extracts,  or  from  powders,  by  the 
addition  of  some  substance  to  give  them  the  necessary  cohesion  and  consistency. 
Pills  generally  weigh  0.1-0.3  G.  (2-5  grs.).  The  U.  S.  P.  determines  the  com- 
position and  size  of  the  official  pills,  so  that  the  doses  can  be  modified  only 
by  ordering  several  pills  to  be  taken  at  one  time.  The  B.  P.  leaves  the  pills 
unformed,  so  that  they  may  be  prescribed  of  any  size.  The  Pilulse  of  the  B.  P. 
really  correspond  not  to  the  Pilulae,  but  to  the  Massae  of  the  U.  S.  P. 

Massce  (U.  S.  P.,  masses,  are  preparations  made  up  of  the  proper  consist- 
ency for  pills.    They  are  invariably  prescribed  in  the  form  of  pills. 

Confediones,  confections  or  electuaries,  are  soft,  solid  preparations  consist- 
ing of  sugar  or  honey  impregnated  with  some  more  active  body. 

Suppositoria,  or  suppositories,  are  intended  for  insertion  into  the  rectum, 
urettu-a,  or  vagina,  and  are,  except  in  one  or  two  cases,  formed  by  mixing  the 
active  ingredient  with  cacao-butter.  Suppositories  for  the  rectum  are  conical 
in  shape  and  weigh  about  a  gramme  (15  grs.).  Those  for  the  urethra  (bougies) 
are  of  the  same  weight,  but  are  pencil-shaped,  while  the  vaginal  suppositories 
are  globular,  and  weigh  about  3  grammes  (45  grs.). 

Pulveres,  powders,  are  simply  dry  substances  in  a  state  of  fine  division. 
Most  of  the  official  powders  are  mixtures  of  several  active  bodies. 

Triturationes  (U.  S.  P.),  triturations,  are  formed  from  powders  by  diluting 
them  with  nine  parts  of  sugar  of  milk. 

Tabelloe,  tablets  (B.  P.)  are  formed  of  chocolate  in  which  an  active  drug  is 
incorporated,  and  weigh  5  grs.  or  less. 

Trochisci,  troches,  or  lozenges,  are  solid  masses,  generally  of  a  flattened  shape, 
and  consist  of  powders  or  other  bodies,  incorporated  in  sugar  and  gum. 

Lamellae  (B.  P.),  or  discs,  are  small  discs  formed  of  gelatin  with  some  gly- 
cerin, each  weighing  jV-i'o  gr-  They  are  impregnated  with  an  active  drug, 
and  are  applied  to  the  conjunctiva  in  order  to  ehcit  the  local  effects. 

Unguenta,  ointments,  salves,  are  soft,  oily  substances  which  are  applied 
to  the  skin  by  rubbing.     (See  page  46.) 


42  INTRODUCTION 

Cernta  (U.  S.  P.),  cerates,  rcsenil)le  ointments,  hut  are  rendered  harder  by 
the  addition  of  wax.    (See  page  46.) 

EmpUidrn,  plasters,  are  adhesive  bodies  of  a  still  harder  consistency  than 
cerates,  and  soften  only  when  heated. 

Chartce,  papers,  are  preparations  of  active  substances  which  are  spread  in 
a  thin  layer  upon  paper. 


Unofficial  Prepar.\tions. 

Cachets,  are  thin  discs  of  dough  of  the  shape  of  a  soup-plate  and  varying 
from  I  in.  to  1|  in.  in  diameter.  When  two  of  them  are  placed  together  wdth 
their  concave  sides  toward  each  other,  they  form  a  receptacle  in  which  powders 
are  dispensed.  The  edges  stick  together  when  they  are  moistened.  A  some- 
what similar  method  of  dispensing  is  in  gelatin  cwpsules,  which  may  be  hard 
or  soft,  and  which  are  made  in  different  sizes.  The  hard  capsule  is  used  for 
solids,  the  soft  for  liquids.  Sometimes  the  latter  contain  as  much  as  15  c.c. 
(^  fl.  oz.),  but  these  are  difficult  to  swallow. 

Tabletke,  tablet  triturates,  or  compressed  tablets,  are  formed  from  fine  powders 
which  are  moistened  and  rendered  coherent  by  some  licjuid  and  then  compressed 
in  moulds.  They  are  generally  about  5  grs.  in  weight,  and  dishitegrate  in  the 
stomach  more  rapidly  than  other  preparations. 

Cataplasmata,  or  poultices,  are  not  official  preparations  now,  but  are  in 
common  use.  They  are  generally  made  of  linseed  meal,  oatmeal,  or  bread 
crumb,  which  is  formed  into  a  paste  with  hot  water,  enclosed  in  thin  cotton 
or  linen  and  applied  to  the  skin.  Mustard  and  other  remedies  may  be  added 
to  the  poultice  in  order  to  induce  special  effects,  and  in  some  cases  a  poultice 
consists  merely  of  drugs  enclosed  in  a  cloth  sack,  as  in  charcoal  or  spice  i)oultices. 

Enemata,  clysmata,  or  clysters,  are  liquid  substances  injected  into  the  rec- 
tum for  their  local  or  general  effects.    (See  page  33.) 


I 


PART  I. 

SUBSTANCES  WHICH  ARE  CHARACTERIZED 
CHIEFLY  BY  THEIR  LOCAL  ACTION. 

This  class  contains  a  very  considerable  part  of  the  drugs  included 
in  the  pharmacopoeias,  although  it  bears  a  smaller  proportion  than 
formerly  to  the  other  classes.  There  is  still,  however,  in  it  a  large 
number  of  drugs  which  have  practically  identical  effects,  and  there  is 
no  question  that  it  might  be  considerably  curtailed  without  loss  to 
therapeutic  practice.  Many  of  its  members  are  irritants,  and  these 
have  been  subdivided  for  convenience  into  groups  according  to  the 
organs  on  which  they  exert  their  chief  action  and  the  purposes  for 
which  they  are  used  in  therapeutics,  as  gastric,  intestinal,  cutaneous 
irritants.  Others  act  as  protectives,  covering  injured  surfaces  (demul- 
cents, emollients),  and  still  others  precipitate  the  proteids  on  the 
surfaces  to  which  they  are  applied  (astringents).  Others  seem  to  act 
chiefly  by  affecting  the  taste  and  the  digestion.  Finally  the  drugs  used 
to  destroy  intestinal  parasites,  and  those  that  are  employed  to  act 
on  bacteria  are  discussed. 

I.     DEMULCENTS. 

A  large  number  of  colloid  substances— chiefly  gums,  dextrins,  sugars 
and  starches — owe  their  use  in  medicine,  not  to  any  changes  they 
produce  in  the  cells  with  which  they  come  in  contact,  but  to  the  fact 
that  they  are  cohesive  and  serve  to  protect  surfaces  mechanically. 
When  they  are  applied  to  a  sensitive  surface,  they  retard  the  movement 
of  fluid  or  air  against  it  and  thus  preserve  it  from  the  effects  of  these 
agents.  This  may  be  illustrated  by  familiar  examples  in  which  the 
taste  of  food  is  altered  by  their  presence,  although  they  have  often  no 
taste  or  odor  in  themselves.  Sugar  dissolved  in  mucilage  tastes  less 
sweet  than  in  water,  and  acids  are  also  less  appreciated,  as  may  be 
observed  in  many  fruits.  For  example,  the  raspberry  contains  more 
acid  and  less  sugar  than  the  currant,  but  in  the  former  the  acid  taste  is 
concealed  by  the  presence  of  large  quantities  of  colloids,  so  that  the 
raspberry  is  regarded  as  a  sweet  fruit,  the  currant  as  an  acid  one.  Even 
cold  is  felt  less  when  a  colloid  substance  is  present  in  the  fluid  swallowed ; 
thus,  ice-cream  or  iced  milk  does  not  feel  so  cold  on  the  tongue  and 
throat  as  frozen  water,  because  the  colloid  protein  substances  form 
a  protecting  layer  over  the  surface,  and  prevent  the  cold  mass  from 
reaching  the  sensory  terminations  so  freel}^  as  it  otherwise  would.     A 

(43) 


44  SUBSTANCES  ACTING  LOCALLY 

iiunihcr  of  experiments  carried  out  by  Tappeiuer'  show  that  other 
organs  may  be  protected  in  the  same  way  by  colloid  solutions.  Strong 
salt  solution  applied  to  a  motor  nerve  first  stimulates  and  then  slowly 
paralyzes  it,  but  Tappeiner  found  that  both  of  these  effects  are  much 
less  marked  if  the  solution  be  made  up  with  mucilage  instead  of  with 
water,  because  the  salt  does  not  reach  the  nerve  so  readily.  In  the 
same  way,  intense  pain  is  caused  in  a  wound  by  strong  salt  solution, 
but  is  much  less  severe  if  the  solution  contain  colloid  material. 

When  demulcents  reach  the  stomach,  they  act  as  protectives  in  some 
measure  so  that  the  reflexes  from  the  epithelium  are  less  active;  and 
irritants  cause  less  inflammation  if  they  are  suspended  in  demulcents 
than  if  they  are  dissolved  in  water;  at  the  same  time  the  presence 
of  colloid  unabsorbable  bodies  may  increase  the  efficiency  of  purgatives 
by  preventing  their  absorption  in  the  upper  part  of  the  bowel.  The 
digestion  of  proteins  outside  the  body  is  retarded  by  the  presence 
of  the  demulcents,  and  probably  this  is  also  true  of  the  process  in  the 
stomach.  Colloid  bodies  also  retard  the  absorption  of  fluids  from  the 
stomach  and  bowel,  and  this  leads  to  a  feeling  of  distention,  which 
is  much  less  marked  if  the  same  amount  of  fluid  be  swallowed  without 
colloid;  for  instance,  water  is  absorbed  more  rapidly  than  milk  or  beer. 

The  colloids  are  absorbed  slowly,  and  probably  only  in  a  condition 
of  semi-decomposition.  After  absorption,  they  are  oxidized  in  the 
tissues  and  therefore  act  as  foods  to  some  extent,  although  their  slow 
absorption  prevents  their  being  of  much  value.  They  have,  of  course, 
no  effect  as  demulcents  after  absorption,  but  the  large  quantity  of  fluid 
with  which  they  are  generally  taken  may  be  of  benefit  in  some  con- 
ditions. 

Demulcents  are  used  to  cover  inflamed  surfaces;  in  tonsillitis,  for 
example,  they  may  be  applied  as  gargles,  or  better  by  sucking  lozenges 
containing  them.  They  are  not  often  applied  externally  for  this  pur- 
pose, as  they  are  liable  to  serve  as  media  for  the  gro^^'th  of  micro- 
organisms. In  gastric  and  intestinal  catarrh  their  use  is  objectionable 
for  the  same  reason,  their  slow  absorption  leading  to  decomposition 
with  the  formation  of  irritants,  which  may  do  more  harm  than  is 
counterbalanced  by  their  protective  action.  Instead  of  demulcents, 
some  of  the  oils,  such  as  olive  oil  (p.  48),  have  been  recommended  as 
protectives  in  disease  of  the  stomach  and  intestine. 

In  acute  irritant  poisoning  the  dennilcents  are  often  of  great  value, 
as  they  protect  the  stomach  wall  from  the  eflfects  of  the  poison.  The 
best  remedy  in  these  cases,  because  the  most  readily  obtainable,  is 
milk  or  white  of  eggs. 

Their  effects  in  retarding  tlie  absorption  of  other  remedies  may  be 
taken  advantage  of.  Thus  opium  and  extract  of  nux  vomica  are  pre- 
scribed when  the  local  action  on  the  bowel  and  stomach  is  desired,  while 
the  pure  alkaloids,  morphine  and  stryclniine  are  administered  for  their 
effects  after  absorption. 

'  Tappeini  r,  Arcliivcs  iiiU'rnat.  <1.  riiaiiinicddyii.,  vol.  x.,  p.  67. 


DEMULCENTS  45 

Demulcents  are  often  given  instead  of  pure  water  in  cases  where  it 
is  desired  to  administer  large  quantities  of  fluid,  as  they  have  more 
"body"  and  are  more  agreeable  to  the  taste.  Thus,  barley  water  or 
some  other  demulcent  may  be  advised  in  order  to  assuage  the  thirst  of 
fever,  or  to  dilute  the  urine  when  it  is  too  concentrated  or  too  acid. 

Demulcents  are  often  used  as  the  basis  of  enemata  which  are 
intended  to  be  absorbed,  because  solutions  containing  colloids  are  less 
irritant  and  therefore  less  liable  to  set  up  peristalsis  than  pure  water. 
For  this  purpose  starch  solution  is  generally  used. 

Some  of  the  gums,  notably  acacia  and  tragacanth,  are  seldom 
advised  as  demulcents,  but  are  often  prescribed  in  order  to  hold  in 
suspension  in  water  such  insoluble  bodies  as  resins  and  oils,  or  to  give 
cohesion  to  pills  and  lozenges. 

Preparations. 

Acacia  (U.  S.  P.),  Acaciae  Gummi  (B.  P.)  (gum  arable),  a  gummy  exuda- 
tion obtained  from  Acacia  Senegal,  consists  of  the  potassium,  magnesium  and 
calcium  salts  of  a  weakly  acid  substance,  arabin,  or  arabinic  acid  (CeHioOs). 
It  is  soluble  in  equal  parts  of  water,  and  is  used  as  a  demulcent,  but  more 
largely  as  a  vehicle  for  other  drugs. 

MuciLAGo  AcACLE  (U.  S.  P.,  B.  P.).    Dose,  16  c.c.  (4  fl.  drs.). 

Syrwpus  Acacice  (U.  S.  P.). 

Tragacantha  (U.  S.  P.,  B.  P.),  a  gummy  exudation  from  various  species 
of  Astragalus,  contains  salts  of  arabin  and  tragacanthin.  Tragacanthin  differs 
from  arabin  in  not  dissolving,  but  merely  swelling  up  into  a  jelly  in  water. 
Tragacanth  is  used  chiefly  to  suspend  heavy  powders  in  water. 

MuciLAGO  Tragacanth^  (U.  S.  P.,  B.  P.).    Dose,  16  c.c.  (4  fl.  drs.). 

Ghjcerimim  Tragacanthce  (B.  P.),  a  solution  of  tragacanth  in  glycerin  and 
water. 

Pubis  Tragacanthce  Compositus  (B.  P.),  contains  tragacanth,  gum  acacia, 
starch  and  sugar.    Dose,  10-60  grs. 

Amylum  (U.  S.  P.,  B.  P.),  or  starch,  may  be  formed  into  a  jelly  by  boiling 
in  water,  and  may  then  be  used  for  the  same  purpose  as  the  demulcents. 

Glyceritum  Amyli  (U.  S.  P.),  Glycerimim  Amyli  (B.  P.),  is  a  jelly  formed  by 
heating  starch  with  water  and  glycerin. 

Amygdala  Dulcis  (U.  S.  P.,  B.  P.),  or  sweet  almonds,  the  seed  of  Prunus 
amygdala  dulcis,  contains  a  fixed  oil  and  emulsin,  a  ferment,  but,  unlike  the 
bitter  almond,  no  amygdalin.  When  triturated  with  water  it  forms  an  emul- 
sion, or  mixture,  which  is  bland  and  demulcent. 

Emulsum  Amygdalce  (U.  S.  P.).    Dose,  120  c.c.  (4  fl.  oz.). 

Pulvis  Amygdalce  Com.posihis  (B.  P.),  contains  sugar  and  acacia  with  almond. 

Sijrupus  Amygdcdce  (U.  S.  P.)  is  formed  from  a  mixture  of  sweet  and  bitter 
almonds,  and  therefore  contains  a  small  proportion  of  prussic  acid.  Dose  4  c.c. 
(1  fl.  dr.). 

Glycyrrhiza  (U.  S.  P.),  Glycyrrhizae  Radix  (B.  P.),  or  liquorice-root,  the 
root  of  Glycyrrhiza  glabra  (var.  gkindulifera),  is  used  as  a  demulcent,  and 
more  largely  to  flavor  medicines.  It  has  a  pleasant,  sweet  taste,  owing  to  the 
presence  of  Glycyrrhizin,  an  acid  glucoside. 

ExTRACTUM  Glycyrrhizae  (U.  S.  P.,  B.  P.).    Dose,  1  G.  (15  grs.). 

Extracturn  Glycyrrhiza'  Purum  (U.  S.  P.).    Dose,  1  G.  (15  grs.). 

Fluidextractuin.  Glyeyrrhizw  (U.  S.  P.),  Extracturn  Glycyrrhizce  Liquidum 
(B.  P.).    Dose,  2  c.c.  (30  mins.). 

PuLvis  Glycyrrhiz.e  Compositus  (U.  S.  P.,  B.  P.),  contains  senna.  Dose, 
4  G.  (60  grs.). 


46  SUliSTAXCES  ACTISG  LOCALLY 

MiSTiRA  Glycyrrhiz.e  Composita  (U.  S.  p.),  "  Broum  Mixture,"  con- 
tains opium,  antinionj'  and  spirits  of  nitrous  ether.    Dose,  8  c.c.  (2  fl.  drs.). 

The  extract  is  largely  used  in  the  form  of  lozenges  for  its  demulcent  action, 
and  is  very  frequently  used  to  make  up  j^ills.  It  is  slightly  laxative,  and  may 
be  used  as  a  pleasant  aperient  for  children;  the  compound  powder  is  more 
reliable  for  this  purpose  owing  to  its  containing  senna,  one  of  the  vegetable 
purgatives.  The  brown  mixture  is  used  in  cough  and  in  catarrh  of  the  air 
passages. 

Numbers  of  other  substances  are  used  as  denmlcents  in  domestic  medicine, 
and  are  found  in  different  pharmacopoeias.  Examples  of  these  are  sassafras 
pith  {Safisafras  Medulla),  slippery  elm  (  Ulmus),  marshmallow  root  {Altluea), 
linseed  (Linum),  barley  (Hordeum),  salep,  verbascum  antl  quince  seeds.  Iceland 
moss  is  a  lichen  (Cetraria  islandica),  and  contains  starch  bodies  together  with 
acids,  which  can  be  removed  by  soaking  in  dilute  alkaline  solutions  for  some 
time.  Irish  moss  or  Carragheen  (Chondrus),  a  seaweed  gathered  on  the  coasts 
of  Ireland  and  Massachusetts,  contains  a  carbohydrate,  carrageenin.  The 
decoction  forms  a  jelly  when  cold,  and  was  formerly  sujiposed  to  form  a 
valuable  food  in  illness,  but  it  is  of  little  ^•alue  for  this  i)urpose,  for  onlj'  about 
iV-f'd  of  the  jelly  is  solid  matter,  the  rest  water.  Couch-grass,  the  rhizome  of 
Agropyrum  re  pens  (Triticum)  is  used  in  the  form  of  a  decoction  as  a  beverage 
in  fever,  and  to  dilute  the  urine.  It  has  a  certain  popular  reputation  as  a 
diuretic  in  suppression  of  the  urine,  calculus,  etc.,  but  this  is  entirely  unmerited, 
for  it  increases  the  urine  simply  by  the  water  given  with  it. 


II.    EMOLLIENTS. 

Emollients  are  bland,  oily  substances  which  are  applied  to  the  skin 
to  protect  it  from  irritation,  and  to  render  it  softer  and  more  elastic; 
they  thus  bear  the  same  relation  to  the  skin  as  the  demulcents  to  the 
mucous  membranes.  Their  effect  in  rendering  the  skin  softer  and 
more  pliable  may  be  due  in  part  to  their  penetration  into  the  surface 
layers,  but  may  also  be  explained  by  the  slight  congestion  induced  by 
the  rubbing  and  massage  used  in  their  application. 

The  older  emollients  were  chiefly  animal  and  vegetable  fats  and 
oils,  but  several  newer  drugs  of  this  class  are  derived  from  petroleum, 
Tlie  eft'ects  of  these  drugs  when  applied  to  the  skin  are  purely  local. 
No  doubt  some  small  percentage  is  absorbed  into  the  tissues,  but  this 
lias  no  known  effect  in  man,  and  although  the  fats  and  oils  are  valuable 
foods  when  taken  internally,  this  plays  no  part  in  tlieir  effects  when 
applied  to  the  skin.  ^.  ^'Jn  ? Jr^A  ' 

The  emollient  preparations  promote  the  absorption  by  the  skin  of 
drugs  dissolved  in  them,  because  they  mix  readily  with  the  thin  layer 
of  oily  sebaceous  matter  which  covers  it.  The  active  substances  dis- 
solved in  them  tlieret'ore  come  into  intimate  contact  with  the  abs()rl)ing 
cells  lining  the  ducts  of  the  glands,  while  watery  solutions  are  separated 
from  the  living  cells  by  a  layer  of  sebum.  If  this  layer  be  dissolved 
oft"  by  alcohol,  watery  solutions  are  also  ai)S{)rbed  rapidly,  and  alcoholic 
solutions  are  al)sorbe<l  as  (juiekly  as  oily  solutions,  because  tlu>  alcohol 
is  miscible  with  the  sebum.  The  absorption  by  the  skin  \aries  con- 
siderabl.N  according  to  the  emollient  used,  and  it  is  found  that  some  drugs 
are  taken  up  more  easil.\  t'ntm  one  ointment,  others  from  another;  the 
dill'erenci-  doubtless  arises  from  the  relative  solubilitx'  in  the  emollient 


EMOLLIENTS  47 

and  ill  the  absorbing  cells,  but  is  still  to  be  investigated.  Aqueous 
solutions  come  into  more  intimate  contact  with  the  cells  of  the  mucous 
membranes  and  with  the  subcutaneous  tissues,  and  are  therefore  more 
readily  absorbed  by  these  than  oily  solutions.  To  ensure  rapid  absorp- 
tion, a  drug  should  be  dissolved  in  some  emollient  if  it  is  to  be  absorbed 
by  the  skin,  in  water  when  it  is  to  be  administered  internally  or  hypo- 
dermically.  Solutions  in  oil  of  such  antiseptics  as  carbolic  acid  are 
much  less  powerful  than  those  in  water,  because  carbolic  acid  being 
more  soluble  in  oil  fails  to  diffuse  into  the  watery  protoplasm  of  the 
microbe,  for  which  it  has  less  affinity.  But  antiseptics  which  are 
more  soluble  in  water  than  in  oils  are  said  to  be  equally  active  in 
both  solvents. 

The  emollients  are  applied  as  protectives  in  abrasions,  cuts,  bruises, 
chapped  hands,  burns;  they  are  less  often  used  alone  in  extensive  skin 
diseases,  but  are  usually  prescribed  in  these  as  the  basis  of  ointments 
in  which  other  remedies  are  incorporated.  There  is  no  question  that 
the  protection  afforded  to  the  part  and  the  exclusion  of  the  air  by 
the  oily  emollient  plays  an  important  part  in  the  action  of  these  reme- 
dies, and  it  seems  probable  that  in  many  cases  equally  good  results 
would  follow  the  application  of  the  emollient  without  any  active 
ingredient. 

The  emollient  ointments  are  also  applied  to  wounds  and  mucous 
membranes  as  protectives  and  also  as  vehicles  for  other  remedies. 
'  Here  they  have  a  more  lasting  effect  than  watery  applications,  which 
are  more  readily  absorbed.  Emollients  are  seldom  applied  to  the 
mouth  because  of  their  unpleasant  oily  taste,  but  the  eye,  nose, 
urethra,  vagina  and  rectum  are  often  treated  with  them. 

Preparations. 

Adeps  (U.  S.  P.,  B.  P.),  lard;    the  prepared  internal  fat  of  the  abdomen 
of  the  pig,  purified  by  washing  in  water,  melting  and  straining. 
_    Adeps  Benzoinatus  (U.  S.  P.),  Adeps  Benzoatus  (B.  P.),  benzoinated  lard, 
IS  prepared  from  lard  by  the  addition  of  benzoin,  which  is  slightly  antiseptic 
and  preserves  it  from  becoming  rancid. 

_   Unguentum  (U.  S.  p.),  ointment,  is  a  mixture  of  lard  and  yellow  wax,  and 
IS  the  basis  of  many  other  ointments. 

Unguentum  Diachylon  (U.  S.  P.)  is  formed  from  lead  plaster  and  olive  oil, 
perfumed  with  oil  of  lavender.  The  lead  is  inert,  the  action  being  identical 
with  that  of  ordinary  ointment. 

Lard  contains  the  ordinary  constituents  of  animal  fats,  stearin,  palmitin, 
and  oleni  and  is  seldom  used  alone,  but  forms  the  basis  of  numerous  ointments. 

Adeps  Lanae  Hydrosus  (U.  S.  P.,  B.  P.),  hydrous  wool-fat,  lanolin,  the  puri- 
fied fat  of  sheep-wool,  mixed  with  not  more  than  .30  per  cent,  of  water. 

Adeps  Lanm  (U.  S.  P.,  B.  P.),  wool-fat  without  water. 

Unguentum  Lance  Compositimi  (B.  P.),  containing  lard,  wool-fat  and  paraffins. 

Lanolin  has  been  used  extensively  in  medicine  only  in  the  last  few  years. 
It  consists  of  cholesterin  esters  with  some  impurities,  "does  not  become  rancid, 
and  differs  from  the  older  fats  also  in  being  miscihle  in  twice  its  weight  of  water 
without  losing  its  ointment  consistency.  Lanolin  is  very  often  used  as  an 
emollient  application,  as  well  as  to  form  a  basis  for  more  active  drugs.  The 
unhydrated  wool   fat   is   too   sticky   to  be  satisfactory.     The  hydrated  form 


48  SUBSTANCES  ACTING  LOCALLY 

is  generally  too  hard  to  be  used  as  an  ointment  and  is  therefore  diluted  with  soft 
paraffin  ('.\  parts)  or  olive  oil  (equal  parts). 

Petrolates  or  Paraffins.  When  the  more  volatile  constituents  of  petroleum 
are  distilled  off,  there  remains  a  number  of  higher  hj^drocarbons,  chiefly  of 
the  marsh  gas  scries,  which  are  used  in  medicine  as  emollients.  The  lower 
of  these  hydrocarbons  are  fluid  at  ordinary  temperatures  and  are  known  as 

Pdrolutuin  Liqiudum  (U.  S.  P.),  Paraffinum  Liquidum  (B.  P.),  a  colorless, 
oily  transparent  liquid  without  odor  or  taste.  When  these  are  removed  there 
remains 

Petrolatum  (U.  S.  P.)  and  Petrolatum  album  (U.  S.  P.),  Paraffinum 
MOLLE  (B.  P.),  soft  petrolate,  vaselin,  which  has  the  consistency  of  an  oint- 
ment, is  yellow  or  white  in  color,  and  is  liquefied  a  few  degrees  above  the  tem- 
perature of  the  blood.  When  the  distillation  is  carried  further,  the  residue 
is  solid  at  ordinary  temperatures,  and  is  knowTi  as 

Paraffinum  (U.  S.  P.),  Paraffinum  Durum  (B.  P.),  or  hard  paraffin,  which 
melts  at  a  somewhat  higher  temperature  than  vasehn. 

Soft  petrolate  is  more  extensivel}'^  used  than  the  others  as  an  emollient  and 
as  a  basis  for  ointments,  and  has  the  advantage  over  the  older  lard  that  it 
does  not  become  rancid;  as  a  general  rule  it  is  too  soft  but  may  be  made  of  the 
proper  consistency  by  the  addition  of  lanolin  or  of  starch  or  zinc  oxide  (equal 
parts);  or  the  Unguentum  Paraffini  (B.  P.),  containing  hard  and  soft  paraffin 
and  beeswax,  maj^  be  employed.  Liquid  i)etrolate  has  been  used  to  dissolve 
irritant  substances  for  subcutaneous  injection,  as  less  pain  is  caused  than  when 
water  is  used. 

Several  Oils  are  also  used  as  emollients. 

Oleum  Olivoe  (U.  S.  P.,  B.  P.),  olive  oil,  a  fixed  oil  obtained  from  the  ripe  fruit 
of  the  olive,  Olea  europsea. 

Oleum  Annjgdake  Expressum  (U.  S.  P.),  Oleum  Amygdalae  (B.  P.),  a  fixed 
oil  expressed  from  bitter  or  sweet  almonds.  It  is  to  be  distinguished  from  the 
volatile  oil  obtained  from  the  bitter  almonds.  The  fixed  oil  contains  no  prussic 
acid. 

Unguentum  Aqu-e  Ros.e  (U.  S.  P.,  B.  P.),  cold  cream,  is  formed  of  white 
wax,  oil  of  almonds,  and  some  borax,  scented  with  rose  water. 

Oleum  Gossypii  Seminis  (U.  S.  P.),  Cotton-seed  oil. 

These  all  resemble  each  other  in  their  composition,  and  may  be  used  as 
emollients.  Olive  oil  is  generally  preferred  to  the  others,  but  is  much  more 
expensive,  and  it  is  probal)le  that  nmch  of  the  so-called  olive  oil  is  really  puri- 
fied cotton-seed  oil,  01i\e  oil  has  been  advised  as  a  cholagogue,  but  has  been 
shown  b}''  more  exact  metliods  of  research  to  have  no  effect  whatever  on  the 
secretion  of  the  bile.  It  sometimes  gives  relief  in  biliary  colic  and  dysentery 
and  in  some  gastric  disorders  accompanied  bj^  pyloric  spasm,  probably  from 
its  acting  as  a  protective  to  the  mucous  membrane  of  the  stomach  and  duo- 
denum and  lessening  the  acid  gastric  secretion.  A  wineglassful  is  given  two  or 
thrc!e  times  a  day  before  meals;  in  these  large  doses  it  possesses  a  high  food  value. 

Cera  Flava  {IL  S.  P.,  B.  P.),  yellow  wax.    Cera  Alba,  white  wax. 

Cetaceum  (U.  S.  P.,  B.  P.),  spermaceti,  obtained  from  the  cachelot  (Phj^s- 
eter  macrocephalus),  one  of  the  whales. 

Sevum  Praeparatum  (U.  S.  P.,  B.  P.),  nnitton  suet,  is  obtained  from  the 
abdominal  fat  of  tlu^  slieep  and  is  of  much  harder  consistency  than  lard. 

These  jireparations  are  not  used  alone,  but  are  often  added  to  the  emollients 
and  ointments  in  order  to  give  them  a  firmer  consistency,  which  is  espcciall}' 
desirable  in  hot  climates  and  in  sununer. 

Ceratum  (U.  S.  P.),  a  mixture  of  8  parts  of  wax  with  7  of  lard. 

Glyckuinum  (U.  S.  p.,  B.  P.),  glycerin,  a  liquid  obtaineil  by  the  decom- 
position of  animal  or  vegetai)le  fats  or  fixed  oils,  and  containing  not  less  than 
95  per  cent,  of  al)solul(!  glycerin,  (MIi(()H)3;  clear,  colorless,  of  a  syrupy 
consistence,  oily  to  the  touch,  with  a  sweet  taste  and  no  odor,  soluble  in  water 
and  alcohol. 


SUGARS  AND  FLAVORING  SUBSTANCES  49 

Glycorin  is  used  as  a  solvent  for  a  number  of  other  drugs,  tlu;  i)reparations 
being  known  as  glycerites  (U.  S.  P.),  glycerines  (B.  P.). 

Glycerin  is  somewhat  irritant  to  the  unbroken  skin,  when  it  is  applied  in 
the  pure  form,  and  even  diluted  glycerin  causes  pain  and  smarting  when  it  is 
applied  to  unprotected  surfaces  such  as  cuts  or  burns,  but  the  pain  soon  dis- 
appears, and  glycerin  then  acts  as  a  protective.  The  irritation  is  due  to  the 
glycerin  abstracting  the  fluids  of  the  tissues  owing  to  its  avidity  for  water. 
Glycerin  and  its  preparations  are  used  very  extensively  as  applications  to  slight 
wounds,  in  irritation  of  the  skin  and  lips  from  exposure  to  cold,  and  in  similar 
conditions.  They  are  often  applied  to  hard,  dry  crusts  on  the  skin  in  order 
to  soften  them  and  permit  of  their  removal. 

Along  with  the  emollients,  or  oily  protectives,  may  be  mentioned 
another  class  of  mechanical  agents,  the  Dusting  Powders.  Any  dry, 
insoluble,  fine  powder  applied  to  irritated  surfaces  of  the  skin,  or 
shght  abrasions,  will  protect  these  from  the  air,  and  from  contact  with 
the  clothes  and  other  sources  of  pressure.  These  powders,  at  the 
same  time,  soak  up  any  secretions,  and  render  the  injured  spot  less 
liable  to  bacterial  infection,  as  they  form  a  more  or  less  impermeable 
crust.  Powders  used  for  this  purpose  should  not  be  absorbed,  or,  if 
absorbable,  should  not  induce  any  toxic  effects.  Those  most  commonly 
employed  are  the  phosphate  and  carbonate  of  lime,  talc  (Talcum, 
Talcum  Purificatum,  U.  S.  P.)  (magnesium  silicate),  Fullers'  earth  and 
kaolin  (aluminum  silicates),  starch,  and  Lijcopodknn  (U.  S.  P.),  which 
consists  of  the  spores  of  Lycopodium  clavatum  (club  moss). 

A  large  number  of  powders  are  used  as  surgical  dressings,  most  of 
them  being  credited  with  more  or  less  antiseptic  power.  In  many 
instances,  however,  their  antiseptic  action  is  so  slight  that  it  would 
appear  that  most  of  their  virtues  are  due  to  their  mechanical  pro- 
perties, and  not  to  their  bactericidal  action. 

III.    SUGARS  AND  FLAVORING  SUBSTANCES. 

Sugars  are  used  in  medicine  chiefly  to  disguise  preparations  of 
unpleasant  taste,  and  in  the  small  quantities  usually  employed  have 
little  further  effect.  In  large  quantities  sugars,  like  other  diffusible 
bodies,  act  as  irritants  to  the  stomach  and  bowel,  and  comparatively 
sniall  quantities  of  some  sugar  substances  possess  an  aperient  action; 
this  seems  to  be  due  to  their  colloid  form,  as  pure  sugar  has  no  such 
effect,  and  it  is  possible  that  they  merely  delay  the  absorption  of  fluid, 
and  thus  cause  softer  evacuations  than  would  otherwise  occur. 

Preparations. 

Saccharum  (U.  8.  P.),  Saccharum  Purificatum  (B.  P.),  sugar. 

Syrupus  (U.  S.  P.,  B.  P.),  a  concentrated  solution  of  sugar.  Syrup  is  the 
basis  of  a  large  number  of  medicated  syrups  of  the  pharmacopoeias.  Sugar 
and  syrup  are  used  exclusively  to  sweeten  mixtures  and  to  aid  in  the  suspen- 
sion of  insoluble  bodies.  In  place  of  ordinary  syrup  many  of  the  flavored 
preparations  may  be  used,  such  as  the  syrups  of  citric  acid,  acacia,  almonds, 
or  of  the  volatile  oil  group. 


50  SUBSTANCES  ACTING  LOCALLY 

Saccharum  Lactis  (U.  S.  P.,  B.  P.),  sugar  of  milk,  lactose,  is  not  so  sweet 
as  ordinary  sufiar,  and  is  much  less  liable  to  delic}uesce,  so  that  it  is  used  largely 
to  give  bulk  to  powders.  It  has  been  said  to  have  diuretic  properties  when 
given  with  large  quantities  of  water,  and  to  cause  purgation  wlien  given  in 
a  more  concentrated  solution.  Asses'  milk  contains  more  lactose  than  cows' 
milk,  and  has  been  recommended  for  its  slight  aperient  action  in  chronic  con- 
stipation. 

Maltum  (l^  8.  P.),  malt,  barley  grain  partially  germinated  and  then  dried. 

Mel,  honey,  and  Mel  Depuratum  (U.  S.  P.,  B.  P.),  or  clarified  honey,  are 
used  to  give  taste  to  mixtures,  and  have  a  very  slight  aperient  action,  so  that 
they  may  be  advised  as  articles  of  diet  in  habitual  constipation.  Some  medi- 
cated honej's  are  used,  of  which  Mel  Rosoe  is  included  in  the  U.  S.  P.,  Mel  Bor- 
acis  in  the  B.  P. 

Syrupus  Glucosi  (B.  P.),  a  mixture  of  liquid  glucose  and  sjo-up. 

A  number  of  saccharine  preparations  with  a  slight  aperient  effect  are  in- 
gredients of  the  preparations  of  the  more  powerful  purgatives.  Thus  manna 
{Manna  U.  S.  P.)  obtained  from  the  flowering  ash,  is  contained  in  the  Infusum 
Sennse  Co.  U.  S.  P.,  and  purging  Cassia  {Cassioe  Pulpa,  B.  P.),  tamarinds  {Tam- 
arindus,  B.  P.),  figs  and  prunes  form  constituents  of  the  confection  of  Seima 
and  other  preparations.  Thej^  are  not  prescribed  alone,  but  the  fruits  may  be 
advised  as  articles  of  diet  where  a  mild  laxative  is  required.  The  tamarind 
pulp  may  owe  its  aperient  action  in  part  to  the  presence  of  tartrates,  citrates, 
malates,  and  other  cathartic  salts.     (See  Saline  Cathartics.) 

Frequently  other  flavors  are  preferred  to  sugar,  which  is  especially 
disliked  in  fever  cases,  as  sweet  fluids  do  not  quench  the  thirst  so 
effectually  as  acids  and  bitters.  INIany  of  the  preparations  of  the 
volatile  oils  and  some  of  the  demulcents  are  used  almost  exclusively 
as  flavoring  agents,  and  in  some  both  sugar  and  volatile  oil  are  com- 
bined, as  in  the  syrups. 

Instead  of  sugar  some  artificial  compounds  have  been  introduced  of 
late  years.     Glusidum  (B.P.),  Benzosulphinidum  (U.S. P.),  or  Saccharin, 

C6H4.  gQ  ^NH,  and  its  sodium  salt,  C6H4:(^ qq    ^NNa,  or  soluble 

saccharin  are  the  best  known  of  these.  Saccharin  is  a  light,  white, 
crystalline  powder,  soluble  in  400  parts  of  water  and  in  25  parts  of 
alcohol.  It  is  about  500  times  as  sweet  as  sugar,  and  gives  a  distinct 
flavor  to  70,000  times  its  weight  of  water.  It  does  not  taste  exactly 
like  sugar,  however,  there  being  a  distinct  flavor  besides  that  of  sweet- 
ness, and  patients  generally  object  to  it  after  a  short  time.  It  has 
been  used  as  a  substitute  for  sugar  in  diabetes,  a  disease  in  which 
sugar  is  to  be  avoided  as  far  as  possible.  Some  writers  state  that  in 
the  presence  of  saccharin  the  digosti\e  ferments  act  more  slowly  than 
usual,  but  the  retardation  is  only  trifling  and  does  not  preclude  the 
use  of  saccharin  in  the  small  quantities  necessary  to  sweeten  the  food. 
Even  very  large  doses  of  saccharin  may  be  injected  intravenousl}'  in 
animals  without  other  eHcct  than  some  depression  and  stu])or. 

Some  pliarmacopoDial  i)n'panitions  are  designed  to  give  color  to  solutions, 
but  arc  seldom  or  never  prescribed,  although  they  are  sometimes  added  by 
the  pharmacist. 

Among  these  are  cochineal  {Coccus,  U.  S.  P.,  li.  P.,  Tinctura  Cocci,  B.  P.) 
and  saffron. 


SIMPLE  BITTERS  51 


IV.      SIMPLE  BITTERS. 


This  group  includes  a  number  of  substances  which  have  Httle  in 
common  except  their  bitter  taste  and  their  comparative  inactivity  in 
the  body.  Several  alkaloids  may  be  placed  in  it,  Berherinc,  Buxine, 
Menispermine  and  Canadine,  for,  although  these  are  poisonous  in  very 
large  quantities,  they  are  harmless  in  those  in  which  they  are  con- 
tained in  the  preparations  used  in  therapeutics.  In  addition  to  these 
there  may  be  placed  in  it  numerous  neutral  bodies,  possessing  an 
intensely  bitter  taste,  but  with  little  or  no  further  action,  such  as  the 
Quassiins,  Columhin  and  a  few  weak  acids  and  glucosides. 

Pharmacological  Action. — These  substances,  or  rather  the  preparations 
containing  them,  are  largely  used  in  therapeutics  in  order  to  increase 
the  appetite,  and  their  administration  is  often  followed  by  a  distinct 
improvement  in  the  digestion  and  an  increase  in  weight. 

Alimentary  Tract. — These  effects  are  explained  by  the  action  of  bitter 
substances  in  increasing  the  secretion  of  gastric  juice,  which  has  been 
shown  to  occur  in  man  and  animals  by  a  number  of  experiments. 
This  is  not,  howe^•er,  through  the  bitters  acting  on  the  gastric  mucous 
membrane  directly,  for  when  they  are  applied  through  a  gastric 
fistula,  they  have  no  specific  action  on  the  secretion.  Pawlow  has 
shown  that  the  chief  factor  that  determines  the  activity  of  the  gastric 
secretion  is  the  odor  and  taste  of  food;  thus  in  dogs  with  oesophageal 
fistulfe,  in  which  the  food  swallowed  does  not  pass  into  the  stomach 
but  escapes  through  a  wound  in  the  oesophagus,  the  taste  and  odor 
of  food  cause  a  profuse  secretion  of  gastric  juice  (psychical  secretion). 
Bitters  given  shortly  before  augment  this  reflex,  and  the  same  effect 
is  seen  when  the  mouth  is  merely  rinsed  with  bitter  solution.  The 
action  of  the  bitters  is  therefore  to  increase  the  psychical  secretion  of 
gastric  juice,  possibly  because  of  the  contrast  offered  by  the  bitter  and 
the  pleasant  tastes.  The  inference  may  be  drawn  that  the  therapeutic 
effects  are  best  elicited  when  the  bitters  are  given  shortly  before  a 
meal,  and  this  accords  with  universal  experience.  And  the  use  of 
the  bitters  is  attended  with  benefit  only  in  cases  in  which  the  gastric 
juice  is  deficient.  The  increase  of  the  gastric  juice  is  followed  as 
usual  by  a  more  active  secretion  by  the  pancreas.  In  addition,  it  is 
to  be  remembered  that  the  improvement  is  largely  subjective,  and  that 
the  bitters  are  capable  of  producing  a  considerable  impression  upon 
patients,  so  that  the  effects  may  be  due  in  part  to  suggestion  and  not 
to  any  real  action  of  the  drug. 

In  comparison  with  their  effects  on  secretion,  the  other  changes  induced 
in  the  aUmentary  tract  by  the  bitters  are  insignificant.  They  have  little  or 
no  effect  on  the  activity  of  the  ferments  in  themselves,  but  the  tannin  and 
colloids  of  the  usual  preparations  may  retard  their  action.  And  they  do  not 
affect  the  growth  of  bacteria  or  yeasts.  Absorjjtion  from  the  alimentary  tract 
and  the  movements  of  the  stomach  and  bowel  are  not  altered  by  their  presence. 
The  salivarjr  secretion  is  generally  augmented  bj'  hitter  tastes,  and  some  increase 
in  the  leucocytes  and  red  cells  of  the  blood  is  said  to  occur  after  their  use. 


52  SUBSTANCES  ACTING  LOCALLY 

In  very  large  quantities  some  of  the  bitters  produce  effects  that  are  obviously 
due  to  their  absorption,  but  these  play  no  part  in  their  therapeutic  effects  and 
have  seldom  or  never  been  elicited  in  man. 

Preparations. 

Gentiana  (U.  S.  P.),  Gentianae  Radix  (B-  P-),  gentian,  the  root  of  Genti- 
ana  lutea,  contains  a  glucoside,  gentiopicrin,  and  a  trace  of  tannic  acid.  1  G. 
(15  grs.). 

ExTUACTiM  Gen'TIAn.e  (U.  S.  p.,  B.  p.).    0.25  G.  (4  grs.).     B.  P.,  2-8  grs. 

Fluidextractum  Geniiaim  (U.  S.  P.).    1.0  c.c.  (15  mins.). 

TiNCTURA  GeiVTIan.e  Composita  (IJ.  8.  P.,  B.  P.),  containing  gentian,  bitter 
orange  peel,  and  cardamom,  4  c.c.  (1  fl.  dr.)  (^-1  fl.  dr.  B.  P.). 

Infimim  Gentiance  Compositum  (B.  P.),  containing  gentian,  bitter  orange 
peel,  and  fresh  lemon  peel,  ^-1  fl.  oz. 

Quassia  (U.  S.  P.),  Quassise  Lignum  (B.  P.),  the  wood  of  Picra^na  excelsa, 
contains  several  neutral  bitter  substances,  resembling  each  other  closely  chem- 
icallv  and  known  as  quassiiiis. 

ExTKACTUM  Ql-assi.e  (U.  S.  P.),  0.065  G.  (1  gr.). 

TiNCTURA  QuASSi.E  (U.  S.  P.,  B.  P.),  2  c.c.  (30  mins.)  (B.  P.,  ^-1  fl.  dr.) 

Infusum  Quassle  (B.  P.),  |-1  fl.  oz. 

Calumba  (U.  S.  P.),  Calumbse  Radix  (B.  P.).  columbo,  the  root  of  Jateor- 
rhiza  palmata,  or  Columba,  contains  columbin,  a  neutral  body,  columbic  acid, 
and  three  alkaloids,  columbamine,  jateorrhizine,  and  palmitine  closely  resemb- 
Hng  berberine. 

TiNCTURA  Calumb.e  (U.  S.  P.,  B.  P.),  4  c.c.  (1  fi.  dr.).    (§-1  fl.  dr.  B.  P.). 

Infusum  Calumbcc  (B.  P.),  ^-1  fl.  oz. 

Chirata  (B.  P.),  Chiretta,  the  plant  Swertia  chirata,  contains  a  glucoside, 
chiratin,  and  ophelic  acid. 

Tinctura  Chiratcc  (B.  P.),  \-l  fl.  dr. 

Infusum  Chirake  (B.  P.),  ^-1  fl.  oz. 

Many  other  remedies  have  been  used  in  medicine,  which  owe  their  reputa- 
tions to  their  bitterness  only.  As  a  general  rule  they  have  been  introduced  as 
possessing  specific  properties  in  some  such  disease  as  gastric  cancer,  but  have 
failed  to  maintain  their  promise  and  gradually  are  recognized  to  be  in  no  way 
superior  to  gentian  and  other  established  bitters.  Their  use  as  bitters  often  forms 
a  i^relude  to  their  complete  abandonment.  Among  these  unnecessary  bitter 
drugs  may  be  mentioned  Taraxacum,  the  root  of  the  dandelion;  Berberis,  the 
rhizome  and  roots  of  the  barberry,  containing  the  alkaloid  berberine;  Pareira, 
the  root  of  Chondrodcndron  tomentosum,  containing  two  alkaloids,  bcbcerine  and 
chondrodine;  Serpriifaria,  snakcroot,  the  rhizome  and  roots  of  two  species  of 
Aristolochia,  containing  an  unknown  bitter  principle  and  an  alkaloid,  aristolo- 
chine,  and  Ilumulux,  hops  with  its  preparation  Lupulin,  a  glandular  powder 
which  contains  a  bitter  neutral  principle,  an  acid  and  resins.  These  still  receive 
recognition  in  the  pharmacopoeias,  if  not  in  practical  therapeutics.  Others, 
which  have  reached  a  further  stage  on  the  path  to  oblivion,  but  which  are 
still  heard  of  occasionally  are  Cusparia  (Angostura  bark),  Xcdandnv  Cortex 
(Bebeeru  bark),  Condivrango  (Marsdenia  Condurango)  anil  Coto. 

Instead  of  the  simple  bitters,  cinchona  and  mix  vomica  jircparatioiis 
are  often  used  in  small  quantities.  Many  of  the  preparations  which 
will  be  enumerated  under  tlie  volatile  oil  series  owe  much  of  their 
ell'cct  to  the  bitter  which  accompanies  the  volatile  oil,  and  in  numerous 
other  pharmacopo'ial  i)rcparati«tns  bitters  ar(>  jircsent,  althou.uli  their 
cllcct  is  lii<i<h-n  1)\  the  action  of  the  druj:  in  other  directions. 

Therapeutic  Uses.  The  bitters  are  used  chiefly  to  increase  the  ai)pe- 
titc    and    tiic  diji;cstion.      In   com alescents,  in   persons  of   sedentary 


SIMPLE  BITTERS  53 

habits,  «ind  occasionally  in  chronic  dyspeptic  conditions  they  are  of 
valnc,  while  in  cases  of  more  acnte  gastric  irritability  and  in  hyper- 
acidity they  may  do  harm  rather  than  good.  (icntian,  Qnassia, 
Calumba  and  Cliirata  are  the  only  simple  bitters  that  are  largely 
used,  and  the  first  is  much  the  most  important.  They  are  generally 
prescribed  as  tinctures,  fluid  extracts  or  other  fluid  preparations. 
The  last  three  may  be  prescribed  with  iron  preparations,  as  they  contain 
little  or  no  tannic  acid  and  thus  cause  no  precipitate.  Pills  are  some- 
times prescribed  with  extract  of  gentian  or  quassia,  but  it  seems  open 
to  question  whether  these  ingredients  have  really  any  effect  when 
given  in  this  form,  as  the  bitter  taste,  on  which  their  action  depends, 
is  largely  concealed.  Compound  tincture  of  gentian  is  sometimes  used 
to  give  flavor  rather  than  for  any  effect  on  the  digestion. 

Quassia  infusion  (10  per  cent.)  is  injected  as  an  enema  in  the  round 
worms  of  children. 

Several  of  the  drugs  mentioned,  such  as  taraxacum  and  gentian,  have  been 
supposed  to  have  a  specific  action  on  the  liver,  but  there  are  no  sufficient 
grounds  for  this  belief.  The  supposed  virtues  of  pareira  as  a  diuretic  and 
of  berberine,  buxine,  and  other  alkaloids  as  substitutes  for  quinine  in  ma- 
laria have  also  proved  to  have  no  foundation,  and  the  popular  reputa,tion  of 
hops  as  a  narcotic  probably  arises  from  its  association  with  alcohol  in  beer. 
Cotoin  and  Goto  bark  are  said  to  have  some  special  effect  in  lessening  diar- 
rhoea, in  addition  to  their  action  as  bitters. 

Bibliography. 

Gottlieb.    Arch.  f.  exp.  Path.,  xxxiii,  p.  261. 

Rieder.    Ibid.,  Ixiii,  p.  303. 

Scanzoni.    Ztschr.  f.  Biol.,  xxxiii,  p.  462. 

Jodlbauer.    Arch,  internat.  d.  Pharmacodyn.,  x,  p.  201. 

Pawlow  u.  Schu7nowa-Simanowskaja.    Arch.  f.  (Anat.  u.)  Phys.,  1895,  p.  53. 

Bmz.    Virchow's  Archiv,  xlvi,  p.  129. 

Jukna.    Arb.  des  pharmak.  Instit.  Dorpat,  iv,  p.  81.     (Condurango.) 

Pohl.    Arch.  f.  exp.  Path.  u.  Pharm.,  xxix,  p.  282      (Aristolochine.) 

Farkas.    Pflilger's  Archiv,  xcii,  p.  61.    (Lupulinic  acid.) 

K.  V.  Bunge.    Arb.  des  pharmak.  Institut.  Dorpat,  xi,  xii,  p.  135.     (Berberine.) 

Mosse  u.  Tautz.     Ztschr.  f.  klin.  Med.,  xliii,  p.  257. 

Ramm.    Historische  Studien  a.  d.  pharmak.  Instit.  Dorpat,  ii,  p.  1. 

Borissow.     Arch.  f.  exp.  Path.  u.  Pharm.,  li,  p.  363. 

Karh.     Deut.  Arch.  f.  klin.  Med.,  Ixxvi,  p.  30.     (Goto.) 

Reichmann.     Ztschr.  f.  klin.  Med.,  xiv,  p.  177. 

Kohert.    International  Congress,  Berlin,  1890,  iv,  p.  58.     (Cetrarin.) 

Biberfeld.     Ztschr.  f.  exp.  Path.  u.  Pharm.,  vii,  p.  569.     (Calumba.) 


Pepper  Group. 

The  pepper  group  comprises  a  few  drugs  wdiich  are  used  for  their 
effect  on  digestion  but  which  have  a  much  more  pungent  taste  than 
the  bitters,  and  cause  marked  irritation  when  they  are  applied  in  large 
doses.  They  thus  stand  midway  between  the  simple  bitters  and 
the  carminative  volatile  oils,  and  are  sometimes  known  as  aromatic 
stomachics. 


54  SUBSTANCES  ACTING  LOCALLY 

Black  Pepper  contains  a  weakly  basic  substance,  Piperine  (wliicli  is  broken 
up  l)y  caustic  alkalies  into  Pipcridiitc  and  Pi])eriiiic  acid),  in  addition  to  a 
volatile  oil  and  a  liitter  pungent  resin.  Piperine  is  insoluble  in  water,  and  has 
therefore  no  taste  when  absolutelj^  pure,  but  is  hot  and  pungent  to  the  taste 
when  it  is  taken  in  solution. 

Pyrethrum,  or  i)eIlitory,  contains  similar  constituents  but  is  scarcely  used 
except  as  an  ingredient  of  insect  powders. 

Capsicum,  or  Cayenne  pepper,  contains  Capsaicin,  a  neutral  body  with  a  hot 
pungent  taste. 

Many  other  plants  contain  irritant  principles  which  have  been  employed  as 
stomachics.  Thus  the  use  of  mustard  as  a  condiment  depends  on  its  forming 
irritant  sulphur  compounds,  but  mustard  is  used  in  medicine  only  as  a  skin 
irritant  and  will  be  discussed  under  that  heading. 

The  horseradish  (Armoracia,  B.  P.)  and  the  formerly  official  scurv'y-grass 
(Cochlearia  officinalis)  resemble  mustard,  and  owe  their  activity  to  their 
containing  similar  or  identical  sulphur  compounds. 

Pepper  and  capsicum  are  largely  used  as  condiments,  and  are  compara- 
tively seldom  prescribed  in  therapeutics,  lioth  are  used  in  domestic  medi- 
cine as  skin  irritants,  and  capsicum  is  prescribed  where  a  strong  stomacliic 
irritant  is  required.  The  tincture  has  been  employed  in  chronic  alcoholism 
in  order  to  provide  a  substitute  for  the  local  irritant  effects  of  spirits  in  the 
stomach. 

Preparations. 

Piper  (U.  S.  P.),  black  pepper,  the  unripe  fruit  of  Piper  Nigrum. 

Oknrcmm  Piperis  (U.  S.  P.),  0.03  G.  (^  gr.). 

Pyrethrum  (I'.  S.  P.),  pellitory,  the  root  of  Anacyclus  Pyrethrum. 

Capsicum,  Cayeiuie  pepi)er,  chillies,  the  fruit  of  Capsicum  fastigiatum 
(U.  8.  P.);    Capsici  Fructus,  the  dried  fruit  of  Capsicum  minimum  (B.  P.), 

Tinctura  Capsici  (U.  8.  P.,  B.  P.),  0.5  c.c.  (8  mins.),  (5-15  mins.,  B.  P.). 

Oleorcsina  Capsici  (U.  S.  P.),  0.03  G.  (^  gr.). 

Fluidcxtnictum  Capsici  (U.  S.  P.),  0.05  c.c.  (1  min.). 

Armoraciae  Radix  (B.  P.),  horseradish  root,  the  fresh  root  of  Cochlearia 
Annoiacia. 

Piper  Methisticum,  or  Kava  Kava,  is  used  in  the  South  Sea  Islands  to  pre- 
pare an  intoxicating  licjuor,  which  according  to  Kesteven,  differs  from  the 
alcoholic  preparations  in  producing  marked  muscular  weakness  without  affect- 
ing the  mental  powers.  Other  observers  state,  however,  that  it  causes  confusion 
and  sleep  very  nmch  as  alcohol  does.  Its  local  action  resembles  that  of  pepper, 
and  like  it,  it  has  been  advised  in  gonorrhcea.  Its  virtues  seem  to  reside  in  two 
resinous  bodies. 

Bibliography. 

Buchheim.    Arch.  f.  exp.  Path.  u.  Pharm  ,  v,  p.  455. 

Jungiit.     Ibid.,  xxiv,  p.  315. 

I/o{j!/H'<.     Il>ici.,  ix,  p.  117. 

Kentcven.     Practitioner,  xxviii,  p.  199. 

Lewin.    Berlin,  klin.  Woch.,  ISSG,  p.  7. 

Cema.    Therapcut.  Gazette,  1891,  p.  7. 

V.    DIGESTIVE  FERMENTS. 

A  iiuinI)cT  of  (lit,'«'stivo  fcrmoiits  have  l)eon  introduced  into  tliera- 
peutics  for  the  treatment  of  fi;astrie  and  intestinal  disorders.  The 
earlier  nienihers  of  the  series  were  proteolytic  ferments,  intended  to 
reinforce  the  i)epsin  of  tlie  stomach,  but  of  recent  years  tlie  amylolytic 
ferments  liave  also  been  stronjrly  advocated. 


DIGESTIVE  FERMENTS  55 

1.  Pepsin. 

The  pharmacopoeial  preparations  of  pepsin  are  generally  obtained 
from  the  pig's  stomach.  It  digests  only  in  acid  solution,  the  best 
results  being  obtained  in  a  solution  of  0.2  per  cent,  of  hydrochloric 
acid.  In  alkaline  solution  it  is  inert,  and  in  fact  is  rapidly  decomposed, 
so  that  when  pepsin  and  alkaline  carbonates  or  bicarbonates  are 
prescribed  together,  the  effects  are  due  to  the  alkalies  only. 

Pepsin  is  used  in  therapeutics  on  the  theory  that  the  stomach  does 
not  secrete  enough  of  the  ferment  in  certain  conditions.  But  it  may 
be  questioned  whether  this  is  true  in  even  a  small  proportion  of  the 
cases  treated  with  pepsin,  for  the  gastric  juice  is  almost  always  capable 
of  digesting  proteins  if  it  is  acid  in  reaction.  In  a  number  of  forms  of 
dyspepsia  the  acid  secretion  is  insufficient,  but  the  ferment  is  almost 
always  present  in  quantity,  for  it  digests  proteins  outside  the  body 
as  soon  as  it  is  acidulated.  Pepsin  is  indicated  then  only  in  the  rare 
cases  in  which  the  contents  of  the  stomach  acidulated  with  hydro- 
chloric acid  fail  to  digest  proteins.  It  is  very  often  administered  in 
other  forms  of  dyspepsia,  and  certainly  does  no  harm,  but  there  is  no 
question  that  it  is  entirely  unnecessary  in  the  great  majority  of  the  cases 
in  which  it  is  prescribed. 

Preparations. 

Pepsinum  (U.  S.  P.,  B.  P.),  a  proteolytic  ferment  obtained  from  the  gland- 
ular laj^er  of  fresh  stomachs  from  healthy  pigs,  and  capable  of  digesting  not 
less  than  3,000  times  its  own  weight  of  freshly  coagulated  egg  albumin.'  It 
is  a  fine,  white,  amorphous  powder  or  thin  scales,  free  from  offensive  odor 
and  having  a  mildly  acid  or  saUne  taste,  usually  followed  by  a  suggestion  of 
bitterness.  0.25  G.  (4  grs.),  (B.  P.  5-10  grs.),  in  powder,  or  in  solution  in 
0.2  per  cent,  hydrochloric  acid. 

Pepsin  is  generally  given  during  or  after  meals.  As  has  been  stated,  it  is  very 
rarely  indicated,  as  the  gastric  juice  almost  always  contains  sufficient  ferment. 

Glycerinum  Pepsini  (B.  P.)  contains  hydrochloric  acid.  A  ffuid  drachm 
represents  5  grs.  of  pepsin.     1-2  fl.  drs. 

Many  other  preparations  of  pepsin  are  used  in  popular  medicine,  to  a  less 
extent  by  the  profession.  Pepsin  wines,  for  example,  are  often  taken  as  tonics 
and  digestives,  but  have  only  the  effects  of  alcoholic  beverages. 


2.  Pancreatic  Ferments. 

The  pancreatic  ferments  have  also  been  introduced  into  thera- 
peutics, generally  in  the  form  of  an  extract  of  the  gland,  imncreatin. 
These  ferments  differ  from  pepsin  in  acting  only  in  alkaline  or  neutral 
solution,  and  besides  digesting  proteins,  form  sugar  from  starch  and 
saponify  and  emulsify  fats.  The  pancreatic  ferments  are  rendered 
inert  by  a  comparatively  short  exposure  to  the  acid  gastric  juice. 

The  value  of  pancreatin  is  even  more  problematical  than  that  of 
pepsin,  for  though  it  would  no  doubt  be  valuable  where  the  digestive 
ferments,  particularly  those  of  the  pancreas,  were  deficient,  this  has 

'  The  B.  P.  preparation  may  be  obtained  from  the  pig,  sheep  or  calf  and  is  required 
to  digest  2500  times  its  weight  of  hard-boiled  white  of  egg. 


56  SUBSTANCES  ACTING  LOCALLY 

not  been  shown  to  occur.  On  the  other  hand,  the  pancreatic  ferments 
are  certainly  destroyed  in  passing  through  the  stomach.  It  has  been 
suggested,  however,  that  they  may  act  in  the  stomach,  if  they  are 
given  before  or  with  tlie  food,  as  the  acid  gastric  juice  is  only  secreted 
slowly,  and  some  time  must  elapse  before  the  pancrcatin  is  rendered 
inert.'  Attempts  have  been  made  to  preserve  the  pancrcatin  from  the 
deleterious  effects  of  the  gastric  juice  by  administering  it  in  capsules 
which  are  dissolved  only  in  the  intestine.  It  is  certainly  possible  that 
the  jiancreatin  may  be  useful  in  certain  cases,  where  the  ferments  of 
the  pancreas  are  absent  and  the  acid  of  the  stomach  so  deficient  as 
not  to  be  destructive,  but  there  is  no  reason  to  suppose  that  this  series 
of  accidents  occurs  at  all  frequently,  and  it  is  impossible  to  diagnose 
inefficiency  of  the  pancreatic  secretion.  Pancrcatin  is  now  used  chiefly 
to  digest  the  food  before  it  is  taken,  about  5  grains  sufficing  for  a  pint 
of  milk.  It  has  been  applied  to  cancerous  tumors  in  the  hope  of 
destroying  the  malignant  tissue,  but  has  not  proved  of  value. 

Preparations. 

Pnncreatinum  (U.  S.  P.),  a  mixture  of  the  enzymes  naturally  existing  in 
the  pancreas  of  warm-blooded  animals,  usually  obtained  from  the  fresh  pan- 
creas of  the  pig.  It  forms  a  yellomsh,  yello\\-ish-white,  or  grayish,  amorphous 
powder,  having  a  faint,  not  disagreeable  odor  and  a  meat-like  taste,  and  is 
slowlv  soluble  in  water.  0.5  G.  (8  grs.),  in  powder  or  in  capsules.  Keratin 
capsules  have  been  proposed  in  order  to  protect  the  pancreatm  from  the  gastric 
juice.  .   .         ,       ,.        . 

Liquor  Pancreatis  (B.  P.),  a  liquid  preparation  coiitaming  the  digestive 
principles  of  the  fresh  pancreas  of  the  pig.  Two  cubic  centimeters  of  the 
solution  ought  to  digest  80  c.c.  of  milk. 

In  connection  with  the  digestive  ferments  may  be  mentioned  ingluvin,  an 
extract  of  the  fowl's  gizzard,  which  was  a  few  years  ago  highly  recommended 
as  a  remedy  in  the  sickness  of  pregnancy,  but  has  proved  entirely  valueless. 

3.  Vegetable  Ferments. 

Besides  these  animal  (Hgestive  ferments,  a  number  of  vegetable  proteolytic 
enzymes  are  known,  and  have  enjoyed  a  more  or  less  short-lived  popularity. 
Probably  manv  more  plant  juices  are  able  to  digest  proteins  than  are  at  present 
gcncrallv  recognized;  thus  many  of  the  bacteria  liquefy  gelatin  and  albumm, 
and  the  insectivorous  plants,  such  as  Drosera  (sundew)  and  Dionea,  secrete 
a  digestive  fluid.  Figs,  pine-apple  {hromclm),  the  scark>t  pimpernal  (Anagellis 
arvensis),  and  many  others  of  the  higlicr  plants  have  been  shown  to  possess 
these  ferments,  but" the  best  known  of  these  is  the  Carica  papaya,  or  j^awpaw, 
which  contains  a  digestive  ferment  known  as  papain,  papaijotiu,  or  pa  paid. 
The  ferment  acts  in  neutral,  shghtly  acid,  or  alkaline  solution  at  the  temperature 
of  the  bcjdy  and  in  the  cold.  It  has  been  used  instead  of  pancrcatin  and  pepsin 
in  disorders  of  the  digestion,  and  also  as  an  anthelmintic.  Dii)htheritic  mem- 
branes have  l)een  treated  by  the  frequent  application  of  pai)ain  solution;  the 
underlying  disease;  was  not  favorably  influenced,  however,  and  the  treatment 
has  been  abandoned.  Papain  solution  has  also  been  injected  by  the  hypo- 
dermic needl(!  into  tumors  anil  abscesses,  with  the  intention  of  digesting  the 
new  growth,  or  accelerating  the  progress  of  the  abscess  toward  the  surface,  but 
the  results  obtained  do  not  encourage  its  further  u.se.  Peptones  are  unques- 
tionably formed  in  the  tumors  when  )iai)ain  is  injected. 

8evcl-al  milk-cur<lling  ferments  have  l)een  found  in  jilants,  but  none  of  tlicm 
have  been  used  in  tluTapeutics. 


VOLATILE  OIL  SERIES  57 


4.  Diastase. 


Several  amylolytic  or  sugar-forniing  tVrnients  have  l)eeii  used  more 
or  less  in  therapeutics,  the  first  of  these  being  the  diastase  or  enzyme 
of  malt,  which  is  known  under  the  names  of  malt  extract,  maltzyme, 
maltine,  etc.  When  grain  is  allowed  to  germinate,  its  starch  is  formed 
into  a  soluble  form  (sugar)  by  means  of  a  ferment  known  as  diastase, 
and  it  was  supposed  that  this  diastase  might  aid  the  digestion  of  starchy 
foods  in  the  body.  When  malt  extract  is  formed  at  a  low  temperature, 
it  unquestionably  contains  diastase  and  is  capable  of  digesting  starch, 
but  many  of  the  extracts  on  the  market  are  quite  inert,  the  ferment 
having  been  destroyed  by  heat.  Those  extracts  are  therefore  devoid 
of  digestive  power,  but  form  a  pleasant,  easily  digested  food.  They 
often  contain  alcohol,  and  are  then  indistinguishable  from  beer  or  stout. 
More  recently,  some  other  sugar-forming  ferments  have  been  brought 
forward,  notably  Taka-diastase  obtained  from  Eurotium  oryzse,  a 
mould  of  the  aspergillus  family;  it  has  been  recommended  in  cases  in 
which  there  is  supposed  to  be  a  deficient  digestion  of  starch.  It  ceases 
to  act  in  the  gastric  juice  as  soon  as  the  acidity  exceeds  0.1  per  cent., 
but  may  be  able  to  digest  a  certain  amount  of  starch  in  the  mouth  and 
stomach  before  it  is  destroyed.  The  question  at  once  arises,  however, 
whether  the  ordinary  digestive  juices  are  ever  unable  to  digest  the 
starch  of  the  food.  And  although  a  new  term,  ''  amylaceous  dyspepsia," 
has  been  introduced  to  indicate  this  class  of  cases,  if  they  should  be 
found  to  exist,  it  must  be  admitted  that  no  satisfactory  evidence  of  their 
existence  has  been  brought  forward  as  yet.  It  is  stated  that  more  starch 
is  found  to  be  digested  in  the  stomach  after  the  administration  of  diastase, 
but  this  seems  to  be  beside  the  point,  for  it  merely  indicates  that  less 
starch  reaches  the  intestine  for  the  pancreatic  juice  to  act  upon.  Until 
it  is  shown  that  in  some  cases  the  digestion  of  starch  by  the  intestinal 
ferments  is  insufficiently  performed,  the  diastase  preparations  would 
seem  to  be  superfluous. 

VI.     VOLATILE  OIL  SERIES. 

The  group  of  volatile,  ethereal,  or  essential  oils  contains  a  large 
number  of  preparations  in  the  pharmacopoeias  of  all  countries.  These 
oils  are  obtained  from  plants  by  distillation,  or  more  rarely  by  pressure, 
and  must  be  distinguished  by  the  student  from  the  fatty  or  fixed  oils, 
which  are  non-volatile.  The  volatile  or  ethereal  oils  are  found  chiefly 
in  the  fruits  and  flowering  parts  of  plants,  and  are  very  widely  diffused 
through  the  vegetable  kingdom,  though  some  orders,  such  as  the 
Labiatfe,  Umbellifera^,  Aurantiacepe,  Cruciferse,  and  Coniferse,  are  pre- 
eminent in  their  production.  They  are  all  strongly  odorous,  and  are 
therefore  used  in  perfumery,  and  to  conceal  nauseous  odors  and  tastes 
in  medicine. 

Their  composition  is  extremely  variable.  The  commonest  constituents  are 
Terpenes,  and  some  oils  contain  these  onlj^,  while  in  a  few  oils  no  terpene  has 


58  SUBSTANCES  ACTING  LOCALLY 

been  found  (Attar  of  Roses).  Terpcncs  are  hydrocarbons  of  the  aromatic 
series,  and  possess  the  general  formula  (C5ll8)n.  The  great  majority  of  them, 
or  the  terpcncs  proi)er  (CioHie),  arc  comlnnations  of  a  dihydrobenzol  with 
prop3'l  and  methyl  (C6ll4(Il2)C3ll7CIl3).  Some  twelve  terpcncs  of  this  for- 
mula are  known,  vaiying  in  their  chemical  structure  and  in  their  stereometrical 
form.  Another  grouj)  of  these  hydrocarl)ons  is  formed  by  the  Sesquiterpenes 
(C16H24),  while  a  few  Ditcrpenes  (C20H32)  are  known.  Some  volatile  oils  consist 
of  these  h\'drocarbons  only,  but  most  of  them  contain  in  addition  some  oxidized 
aromatic  substances,  such  as  phenols,  ketones,  aldehydes,  acids,  and  their 
compounds;  as  instances  of  these  may  be  cited  camphor,  thujon  (from  oil  of 
absinthe),  sabinol  (oil  of  savine),  safrol,  thymol,  eucalyptol,  myristicin  and 
vanillin.  Many  of  these  oxidized  products  crystallize  out  when  the  volatile 
oil  is  cooled  sufficiently,  and  especially  on  long  standing,  and  the  resulting  solid 
is  known  as  a  Steawpicne,  while  the  fluid  remaining  is  sometimes  called  Ekcop- 
tene.  The  oils  containing  oxj'gen  are  not  so  volatile  as  the  pure  hydrocarbons, 
but  the  odor  is  often  due  cliiefly  to  the  oxidized  substances.  A  very  few  oils 
contain  nitrogenous  bo(Ues,  generall}^  in  the  form  of  cyanides,  while,  on  the  other 
hand,  the  majority  of  the  volatile  oils  of  the  Cruciferse  contain  sulphur  bodies, 
which  lend  them  a  pungent  disagreeable  odor,  quite  different  from  that  of  the 
other  oils. 

The  volatile  oils  are  generally  clear,  colorless  fluids,  although  some 
of  them  are  green  or  blue  in  color.  After  long  keeping  they  often 
acquire  a  yellowish  color  and  an  acid  reaction,  from  the  formation  of 
resins.  They  are  generally  light,  sparkling  fluids,  but  the  oils  of  copaiba 
and  cubebs  are  more  viscid.  They  are  insoluble  in  water  except  in  very 
small  amount,  which,  however,  is  enough  to  lend  their  characteristic 
odor  to  the  solution;  in  strong  alcohol,  ether,  benzol,  chloroform,  and 
fixed  oils,  they  are  freely  soluble. 

Many  of  the  plants  from  which  the  volatile  oils  are  obtained  possess 
other  active  constituents,  such  as  bitters,  and  as  many  of  the  prepara- 
tions used  in  therapeutics  are  formed,  not  from  the  distilled  oils,  but 
from  the  crude  parts  of  plants,  it  must  be  noted  that  the  oil  is  not  the 
only  active  principle  in  them. 

Action  Externally. — ^The  volatile  oils  all  possess  antiseptic  properties, 
which  arc  doubtless  due  in  part  to  their  volatility  and  their  solubility 
in  lipoids  enabling  them  to  penetrate  readily  into  protoplasm.  Many 
of  them  ai)pear  to  be  more  germicidal  than  carbolic  acid  in  favorable 
circumstances,  but  they  are  generally  too  insoluble  in  water  to  be 
employed  easily  in  surgery. 

Applied  to  the  skin,  they  cause  redness,  itching  and  warmth,  owing 
to  a  l(x-al  dilatation  of  the  vessels,  which  may  be  due  to  the  penetration 
of  the  oil  to  tlic  cutaneous  arterioles  or  veins,  or  to  a  local  reflex  from 
the  irritated  terminations  of  the  sensory  nerves.  When  painted  on  the 
mucous  membranes,  such  as  those  of  the  eye  or  nose,  or  on  wounds,  the 
volatile  oils  cause  similar  irritation,  which  is  betrayed  by  redness  and 
congestion,  ])ain  and  smarting. 

Action  on  the  Alimentary  Canal.  Strong  solutions  of  the  oils  have 
generally  a  hot,  burning  taste,  and  if  kept  in  the  mouth,  cause  redness 
and  irritation  of  the  mucous  membranes,  although  some  of  them  induce 
a  sense  of  coohiess  at  first.     At  tlic  same  time  the  organs  of  smell  are 


VOLATILE  OIL  SERIES  59 

affected  by  tliese  oils,  which  are  ahnost  all  possessed  of  characteristic 
odors.  The  irritation  of  the  mouth  leads  to  a  reflex  secretion  of  saliva, 
which  is  often  very  profuse.  The  antiseptic  action  of  the  oils  is  exercised 
in  the  mouth  as  elsewhere,  and  may  have  a  beneficial  effect  in  some 
conditions. 

On  passing  into  the  stomach,  the  oils  cause  the  same  sensation  of 
warmth  in  that  organ,  and  this  is  accompanied  by  a  sense  of  well- 
being  and  comfort,  the  appetite  is  often  increased,  and  any  feeling  of 
distention  after  meals  is  relieved.  This  is  often  attended  by  the  eruc- 
tation of  quantities  of  gas.  Substances  which  produce  these  effects  in 
the  stomach  are  known  as  carminafives,  and  many  explanations  of 
their  action  have  been  oft'ered.  The  antiseptic  action  may  occasionally 
play  a  part  in  the  carminative  action,  and  possibly  the  secretion  may  be 
encouraged  by  the  slight  irritation  and  by  the  agreeable  odor  and  taste; 
the  activity  of  the  ferments  is  rather  retarded  than  augmented.  The 
movements  of  the  stomach  are  distinctly  lessened  by  even  small  quan- 
tities of  the  volatile  oils,  and  the  muscle  relaxes.  This  may  relieve  the 
feeling  of  distention  and  allow  the  escape  of  the  contents  by  arresting 
spasmodic  contractions  of  the  sphincters;  the  action  appears  to  be  a 
direct  one  on  the  muscle  of  the  walls. 

In  the  intestine  the  volatile  oils  in  small  quantities  also  lessen  the 
contraction  of  the  muscle  walls  and  this  often  relieves  flatulence  and 
distention  and  lessens  the  spasms  which  cause  colic.  Small  quantities 
are  often  incorporated  in  the  preparations  of  the  more  powerful  pur- 
gatives to  lessen  the  pain  and  griping  which  these  are  liable  to  induce. 

Excretion. — Many  of  the  terpenes  are  oxidized  to  phenols  in  the 
body  and  are  then  excreted  in  the  urine,  for  the  most  part  in  combina- 
tion with  glycuronic  or  sulphuric  acid.  Traces  pass  out  in  the  expired 
air  and  impart  an  odor  to  the  breath.  The  urine  also  contains  some  in 
a  free  form  and  may  thus  smell  of  the  original  oil  or  of  some  of  its 
derivatives.  Some  of  the  constituents  of  the  oils  are  oxidized  to  acids 
and  excreted  in  the  urine  as  salts. 

In  the  course  of  excretion,  some  of  the  oils  cause  irritation  of  the 
lungs  and  kidneys,  so  that  some  of  them  are  employed  to  increase  the 
bronchial  secretion,  while  others  have  a  distinct  diuretic  action.  This 
irritant  action  is  of  course  not  confined  to  the  tissue,  but  extends  to 
microbial  guests,  so  that  some  of  the  volatile  oils  are  given  internally 
almost  exclusively  for  their  antiseptic  action  in  the  urine. 

Poisoning. — The  various  oils  differ  a  good  deal  in  their  activity 
while  resembling  each  other  closely  in  the  general  characters  of  their 
effects.  All  of  them  may  produce  marked  irritation  of  the  stomach 
and  bowel  when  given  in  large  quantities,  but  the  oils  of  tansy,  sage, 
and  English  pennyroyal  are  distinguished  especially  by  the  violent 
inflammation  they  cause,  and  by  the  frequency  with  which  fatal  poison- 
ing occurs  from  their  use.  The  symptoms  are  those  of  acute  gastric, 
intestinal,  and  often  renal  irritation — vomiting,  purging,  acute  pain 
in  the  abdomen,  blood  in  the  stools  and  in  the  vomited  matter,  collapse, 
weakness  of  the  pulse  and  respiration,  anuria,  or  albumin  and  blood 


00  SUBSTANCES  ACTING  LOCALLY 

in  the  urine,  and  convulsive  attacks  ending  in  coma  and  death.  Great 
hypenemia  of  the  abdominal  organs,  often  hlood  in  the  peritoneal 
cavity,  and  sometimes  acute  inflammation  of  the  kidney  are  the  chief 
post-mortem  appearances.  The  hypera'mia  and  congestion  of  the 
organs  of  the  abdomen  may  cause  abortion  in  pregnancy,  or  increase 
the  menses,  and  in  the  majority  of  cases  of  poisoning,  these  oils  have 
been  taken  with  the  object  of  inducing  abortion.  In  many  instances, 
however,  the  drug  has  proved  fatal  without  this  end  being  achieved. 

General  Action.— The  small  quantities  of  volatile  oils  administered  in  ordi- 
naj-y  mediciual  use  pass  through  the  tissues  without  modifying  them  percept- 
ibly, their  only  effects  arising  in  the  organs  by  which  they  are  absorbed  and 
excreted.  lu  large  quantities,  however,  some  of  them  (the  oils  of  wormwood, 
nutmeg,  sage,  saviue  among  others)  produce  symptoms  from  a  direct  action  on 
the  central  nervous  system,  which  is  first  stimulated  and  then  depressed. 

The  relative  importance  of  these  two  stages  differs  in  different  oils,  some, 
e.  g.,  turpentine  oil,  causing  only  a  transient  excitement,  followed  by  marked 
weakness  and  depression,  while  others,  such  as  the  oil  of  absinth,  cause  very 
marked  excitement  and  convulsions.  The  activity  of  the  oils  as  nervous  poisons 
also  varies  greatly,  some  producing  only  insignificant  effects  on  the  central 
nervous  system  compared  with  those  from  their  local  action,  while  in  others, 
such  as  the  oil  of  absinth  or  wormwood,  the  symptoms  from  the  nervous  system 
predominate  in  cases  of  poisoning.  As  a  general  rule  the  higher  divisions  of  the 
central  axis  are  affected  more  than  the  lower,  and  epileptiform  or  clonic  convul- 
tions  may  be  induced  (camphor),  or  tremors  similar  to  those  described  under 
carbohc  acid  and  presumably  of  similar  origin  (saf rol  and  nutmeg  oil) .  In  many 
cases  a  combination  of  excitement  and  ataxia  is  observed,  the  animal  moving 
about  restlessly,  but  being  unable  to  balance  itself.  In  the  later  stages  of 
poisoning  the  spontaneous  movements  cease,  while  the  excitation  of  the  lower 
centres  still  persists,  and  wild  convulsive  movements  accompany  the  final  arrest 
of  the  respiration.  The  respiratory  centre  is  finally  depressed,  but  this  depres- 
sion is  often  preceded  by  stimulation,  the  breathing  increasing  both  in  rapidity 
and  in  volume.  The  vasomotor  centre  undergoes  similar  changes,  the  blood- 
pressure  falling  from  some  oils  immediately,  from  others  only  after  a  preliminary 
increase. 

The  heart  does  not  seem  to  be  affected  by  most  of  the  volatile  oils,  except 
indirectly  from  the  collapse  and  shock.  The  frog's  heart  perfused  with  Ringer's 
solution  containing  a  volatile  oil  is  often  accelerated,  but  soon  becomes  slow  and 
weak. 

Involuntary  Jiiuscle  suspended  in  Ringer's  solution  containing  even  small 
amounts  of  volatile  oil  ceases  its  rhythmical  movements  and  relaxes,  apparently 
from  a  direct  action  of  tho.se  bodies  on  the  nniscle  fibre.  The  same  action  is 
seen  in  the  ntenis  suspended  in  this  way,  so  that  it  seems  unlikely  that  these 
oil.s  cause  any  contraction  of  this  organ  directly  such  as  would  explain  their  use 
as  aljortifacients. 

Home  of  the  constituents  of  the  oils  (pulegon,  myristicin,  safrol)  cause  fatty 
degeneration  of  various  organs,  especially  of  the  liver  and  kidney,  while  others 
of  very  similar  constitution  ha^•e  no  such  effect. 

Most  of  the  oils  are  poisonous  to  the  protozoa  in  fairly  dilute  solutions;  as 
a  general  rule  the  moAcmcnts  of  these  organisins  are  accelerated  by  \ery  small 
quantities  of  the  oils.  The  protozoa  are  much  more  susceptible  to  the  oils  than 
the  bacteria,  some  of  which  contiime  to  live  in  5  per  cent,  solutions. 

Although  these  general  effects  of  the  volatile  oils  have  no  therapeutic  im- 
portance, the  frequent  occurrence  of  ejjilepsy  and  insanity  in  habitual  absintii 
drinkers  and  (K-casionai  poisoning  from  others  of  the  si-ries  have  given  them 
some  practical  interest. 


VOLATILE  OIL  SERIES  61 

1.  Volatile  Oils  Used  as  Flavoring  Agents  and  Carminatives. 

As  regards  their  use  as  flavoring  agents  but  little  need  be  said,  one 
preparation  is  used  by  one  physician,  another  by  another,  and  the 
selection  is  largely  a  matter  of  custom  and  taste.  The  orange  prepa- 
rations are  probably  more  generally  appreciated  by  patients  than  any 
others.  Carminatives  are  used  only  when  no  marked  irritation  of  the 
stomach  or  intestine  is  present,  in  cases  where  the  gastric  juice  seems 
unable  to  cope  with  the  food  ingested,  especially  in  persons  of  seden- 
tary habits.  In  cases  of  colic,  flatulence  and  abdominal  distention, 
they  are  often  of  use,  provided  that  these  are  not  due  to  peritonitis 
and  other  inflammatory  diseases.  Several  of  them  have  been  employed 
as  surgical  antiseptics,  but  they  are  more  widely  used  as  parasiticides 
for  scabies,  pediculi,  etc.  Some  of  the  oils,  such  as  oil  of  cloves,  are 
used  in  dentistry  to  relieve  pain,  and  also  for  their  antiseptic  action; 
the  relief  of  pain  is  due  to  their  paralyzing  the  exposed  nerve  ends  after 
a  preliminary  irritation.  Eucalyptus  has  been  advised  in. septic  con- 
ditions and  in  malaria  but  is  of  no  value  in  these  conditions;  its  chief 
constituent,  eucalyptol  (CioHisO),  is  equally  devoid  of  any  special 
virtues  to  distinguish  it  from  the  other  volatile  oils.  Volatile  oil  prepa- 
rations are  sometimes  given  internally  in  the  hope  that  in  their  excretion 
through  the  lungs  they  will  exercise  an  antiseptic  action  in  pulmonary 
disease,  but  the  traces  excreted  in  this  way  are  quite  incapable  of  any 
noticeable  effect  on  microbial  growth,  and  the  tubercle  bacillus,  against 
which  these  measures  are  most  frequently  directed,  appears  to  be 
peculiarly  resistant  to  the  action  of  this  group  of  remedies.  They  are 
frequently  inhaled  with  a  similar  object.  Some  of  them  have  been  used 
as  anthelmintics  to  destroy  tapeworm  in  the  intestine,  and  thymol 
has  recently  proved  very  effective  in  destroying  the  intestinal  parasites 
in  uncinariasis  (see  Thymol).  Externally  some  of  them  are  used  as 
mild  skin-irritants,  generally  in  the  form  of  spirits.  Arnica  has  a 
great  popular  reputation  as  a  stimulating  local  remedy  in  bruises  and 
sprains,  although  it  has  no  specific  action  and  is  in  no  way  preferable 
to  the  other  members  of  the  series. 

The  volatile  oils  are  largely  used  as  flavors  in  cookery  and  sweet- 
making,  and  are  important  constituents  of  many  of  the  popular  liqueurs, 
and  therefore  have  a  certain  dietetic  importance. 

Preparations. 

Crude  Drugs. — Many  of  the  pharmacopoeial  preparations  are  whole  plants, 
seeds,  leaves,  or  flowers,  and  are  never  prescribed,  although  some  of  them 
are  used  in  jjopular  medicine  in  the  form  of  infusions  or  "teas."  The  virtues 
of  these  old-fashioned  remedies  lie  perhaps  more  in  the  large  draughts  of  warm 
water  than  in  the  traces  of  volatile  oil  which  they  contain,  but  the  presence 
of  the  latter  prevents,  to  some  extent,  the  nausea  produced  bj^  warm  water 
alone.  These  infusions  are  used  to  induce  perspiration  in  fevers  or  chills, 
as  diuretics,  or  to  relieve  colic  and  griping,  and  generall}^  contain  about  a 
tablespoonful  of  the  herb  to  one  or  two  cupfuls  of  water.  Those  most  fre- 
quently used  for  this  purpose  are  peppermint  and  spearmint  leaves  and  tops 


G2  SUBSTANCES  ACTING  LOCALLY 

{Mentha  Pipcrila  and  Mentha  Viridis,  U.  S.  P.);  Coriander  seeds  {Corian- 
drum,  U.  S.  P.,  Coriandri  Fmdus,  B.  P.);  Chamomile  flowers  {Anthcmis, 
U.  S.  P.,  and  Matricaria,  U.  S.  P.);  Anise  {Anisu7n,  U.'S.  P.,  the  fruit  of  Pini- 
pincUa  anisum);  Elderflowcr  and  Horehound  {Marmbium,  U.  S.  P.,  leaves 
and  tops).  In  different  countries,  ho\ve^Tr,  the  constituents  of  the  hcrbahst 
receipes  vary  according  to  the  local  flora.  The  U.  S.  Pharmacopoeia  recog- 
nizes a  number  of  other  crude  drugs  of  this  group,  but  as  these  are  seldom 
or  never  prescribed,  they  need  only  be  enumerated  here:  Rosa  Gallica  (red 
rose  petals).  Eucalyptus,  Limonis  Cortex  (lemon  peel),  Aurantii  Didcis  Cor- 
tex, Aurantii  Amari  Cortex  (sweet  and  bitter  orange  pce\),Canjophyllus  (cloves), 
Pimenta  (allspice),  Cinnamomum  (cinnamon),  Sassafras  (sassafras  bark), 
Fwniculum  (fennel),  Vanilla  (vanilla),  Cardamonmm  (cardamom),  Carum 
(caraway),  Myristica  (nutmeg).  Salvia  (sage),  Ariiica,  and  Zingiber  (ginger). 
The  British  Pharmacopoeia  is  less  lavishly  supplied  with  these  little  used  crude 
drugs.  It  contains  Coriandri  Fructus  (coriander  seeds),  Aurantii  Cortex 
Recens  and  Siccatus  (fresh  and  dried  orange  peel),  Cinnamomi  Cortex  (cm- 
namon  bark),  Cardamomi  Semina  (cardamom  seeds),  and  Zingiber  (ginger). 

Bitter  Almonds  (Amygdala  Amara,  U.  S.  P.,  B.  P.)  may  be  mentioned  here, 
as,  although  they  contain  no  volatile  oil  in  themselves,  one  is  formed  from  them 
when  they  are  bruised  in  water.  They  contain  a  glucoside,  amygdalin,  arid 
a  ferment,  emulsin,  which,  in  the  presence  of  water,  decomposes  the  amygdalin 
into  dextrose,  prussic  acid,  and  benzaldehyde. 

Amygdalin.  Dextrose.         Prussic  acid.         Benzaldehyde. 

C20H27NO11     +    3H2O    =    2(C6Hi206)     +    HCN     +    C-HsO     +    H2O 

The  prussic  acid  and  benzaldehyde,  which  are  probably  in  combination  and 
not  merely  mixed  together,  are  known  as  the  oil  of  bitter  almonds,  which  is 
much  more  poisonous  than  the  other  volatile  oils,  owing  to  its  containing 
prussic  acid.  Emulsin  is  also  contained  in  the  sweet  almond,  but  no  amyg- 
dalin, so  that  no  prussic  acid  is  formed  when  it  is  pounded  in  water.  The 
fixed  oil  of  almonds  is  formed  from  bitter  and  sweet  almonds,  but  contains 
no  prussic  acid.  Laurel  leaves,  and  the  bark  of  the  Virginian  prune,  or  cherry 
(Prunus  Virginiana,  U.  S.  P.,  Prxini  Virginiana'  Cortex,  B.  P.),  also  contain 
amygdalin,  or  some  nearly  related  substance,  and  emulsin,  and  form  benzalde- 
hyde and  prussic  acid  when  rubbed  up  with  water.  The  Mrginian  cherry 
])ark  has,  however,  a  more  bitter  taste  than  the  others,  from  the  presence  of  a 
resin  or  some  otlicr  imknown  body. 

The  Volatile  Oils  themselves  are  also  represented  in  unnecessarily  large 
numbers  in  tli(>  jiharmacopocias. 

U.  S.  P. — Oleum  Mentha.  Piperita;  (oil  of  jieppermint),  01.  Mentha:  Viridis 
(spearmint),  01.  (kiultherioi  (wintergreen),  01.  Lavandidw  Florum  (lavender), 
01.  Euccdypti  (eucalyptus),  01.  Limonis  (lemon  peel),  01.  Aurantii  Corticis 
(orange  peel),  Oleoresina  Zingiberis  (ginger),  01.  A)nygdala:-  Amarcc  (bitter 
almonds),  01.  Caryophylli  (cloves),  01.  PimenUv  (allspice),  01.  Cari  (carawaj'), 
01.  Cinnamomi  (cinnamon),  01.  Coriandri  (coriander),  01.  Cajuputi  (cajuput), 
01.  Sa-^safras  (sassafras),  01.  Anisi  (anise),  01.  Fa^niculi  (fennel),  01.  Rosmarini 
(rosemary),  01.  Iledeoma;  (pennyroyal),  01.  Juniperi  (juniper),  ()/.  Rosa;  (oil, 
attar  or  otto  of  roses),  01.  Betulce  (birch),  01.  Thy  mi  (thyme),  01.  Myristicce 
(nutmeg).     Dose  0.2  c.c.  (3  mins.). 

B.  P. — Oleum  Anethi  (oil  of  dill),  01.  Anisi  (anise),  01.  Cajuputi  (cajuput), 
01.  Carui  (caraway),  01.  Caryophijlli  (cloves),  0/.  Cinnamomi  (ciimamon), 
01.  Coriandri  (coriander),  01.  Eucalypti  (eucalyptus),  01.  Lavandula'  (lavender), 
01.  Limonis  (lemon),  01.  Mentha'  Piperittv  (pe])permint),  01.  Myristicw  (nut- 
meg), 01.  Rosmarini  (ro.semary).     Dose  .^-3  mins. 

The  majority  of  these  oils  resemble  each  other  very  clo.sely  in  their  effects 
and  require  no  special  conmicnt.  Oil  of  roses  is  so  expensive  that  it  is  never 
used  in  medicine,  especially  a,'^  it  has  no  special  advantages  over  the  others. 


VOLATILE  OIL  SERIES  G3 

The  oils  of  rosemary,  juniper,  and  savine  are  more  irritant  than  the  others, 
and  are  seldom  used.  The  oils  of  wintergreen  and  of  birch  consist  mainly 
of  methyl-salicylate,  and  may  be  used  instead  of  the  other  salicylates.  Nut- 
meg and  mace  oils  are  more  poisonous  than  the  others,  not  from  their  local 
irritant  action  so  much  as  from  their  effects  after  absorption.  Oil  of  bitter 
almonds  contains  a  very  variable  amount  of  prussic  acid  and  therefore  cannot 
be  substituted  for  the  other  volatile  oils,  but  its  preparations  are  so  dilute  as 
to  be  devoid  of  all  danger. 

The  volatile  oils  themselves  are  comparativel}^  little  used.  A  single  drop 
may  be  added  to  powders,  pills  or  solutions  to  give  a  pleasant  odor,  and  their 
presence  in  tooth  powders  renders  these  more  or  less  strongly  antiseptic.  Oc- 
casionally they  are  given  in  cases  of  colic  or  in  chill  by  pouring  a  few  drops  on 
a  piece  of  sugar  which  is  sucked. 

Spiritus  are  formed  from  many  of  the  volatile  oils  by  dissolving 
them  in  alcohol,  sometimes  with  the  addition  of  water  and  sometimes 
with  some  of  the  crude  drugs,  so  that  the  preparation  is  really  a  mixture 
of  tincture  and  spirit.  The  spirits  or  essences  of  the  volatile  oils  are 
used  very  largely  as  flavoring  agents  in  mixtures  for  internal  use, 
and  are  often  added  to  external  applications  to  lend  them  odor.  They 
may  also  be  prescribed  where  alcohol  is  indicated  but  is  distasteful  to 
the  patient;  the  spirits  of  the  volatile  oils  contain  nearly  double  the 
amount  of  alcohol  in  brandy,  and  have  to  be  diluted  accordingly. 
Any  of  them  may  be  used  as  carminatives,  but  the  spirits  of  pepper- 
mint, cinnamon,  anise  and  lavender  are  more  frequently  used  for 
this  purpose  than  the  others.  Spirit  of  juniper  is  often  given  as  a 
diuretic,  either  alone  or  along  with  other  drugs.  Spirit  of  rosemary 
is  generally  used  externally.  Many  of  the  common  perfumes  are 
spirits  of  different  volatile  oils;  thus  eau  de  Cologne  contains  the  oils 
of  bergamot,  lemon,  rosemary,  lavender  and  orange-flow'er,  along  with 
acetic  ether  and  alcohol. 

The  dose  of  the  spiritus  as  carminatives  is  2-4  c.c.  (30-60  mins.) 
They  are  often  prescribed  along  with  other  stomachics,  such  as  nux 
vomica,  cinchona,  or  the  bitters. 

U.  S.  P. — Spiritus  Amxjgdaloe.  Amarce,  Spir.  Anisi,  Spir.  Aurantii  Com. 
positus  (containing  the  oils  of  orange  peel,  lemon,  coriander,  and  anise),  Spir- 
Cinnamomi,  Spir.  Gaultherice,  Spir.  Juniperi,  Spir.  Juniperi  Compositus  (con- 
taining oils  of  juniper,  caraway,  and  fennel;  8  c.c.  (2  fl.  drs.).  Spir.  Lavan- 
dulce,  Spir.  Menthoe  Piperitce,  Spir.  Menthce  Viridis. 

Elixir  Aromaticum  and  Elixir  Adjuvans  are  preparations  of  the  Spir.  Aurantii 
Compositus,  which  are  used  exclusively  as  flavors. 

B.  P. — Spiritus  Anisi,  Sp.  Cajuputi,  Sp.  Cinnamomi,  Sp.  Juniperi,  Sp. 
Lavandulce,  Sp.  Menthce  Piperitce,  Sp.  Myristicce,  Sp.  Rosmarini. 

Aquae. — The  volatile  oils  are  very  insoluble  in  w^ater,  but  when  they 
are  shaken  in  it,  enough  remains  in  the  water  to  give  it  the  odor  and 
taste  of  the  oil.  In  the  process  of  obtaining  the  oils  from  the  crude 
drugs  by  distillation,  some  oil  is  held  by  the  water,  and  a  number  of 
these  waters  (aquae)  are  contained  in  the  pharmacopoeias.  They  are 
used  as  substitutes  for  distilled  water  in  making  up  prescriptions,  the 
small  quantity  of  volatile  oil  serving  merely  to  give  a  pleasant  odor 
and  taste. 


64  SUBSTANCES  ACT  IXC!  LOCALLY 

U.  S.  p.— Aqua  Atiisi,  Aq.  Aurantii  Flor.  and  Aq.  Aurantii  Florum  Fortior 
(the  latter  containing  twice  as  much  vohitile  oil  as  the  former),  Aq.  Cinna- 
momi,  Aq.  Fwniculi,  Aq.  Menth.  Piperita),  Aq.  Meiith.  Viridis,  Aq.  Rosoe, 
Aq.  Rosa;  Fortior  (the  latter  twice  as  strong  as  the  other. 

B.  P. — Aqua  Anethi,  Aq.  Anisi,  Aq.  Aiirantii  Floris,  Aq.  Cinnamomi,  Aq, 
MentfuB  Piperitce,  Aq.  Rosce. 

Some  of  the  preparations  containing  volatile  oils  are  derived  not 
from  the  oil  itself,  but  from  the  crude  drug,  and  therefore  contain 
non-volatile  substances  which  are  generally  absent  from  the  prepara- 
tions alread}^  mentioned.  As  a  general  rule  these  non- volatile  bodies 
are  inactive,  but  in  some  cases,  bitters  or  resins  are  contained  in  the 
preparations,  and  may  influence  their  action.  Thus  a  bitter  glucoside, 
hesperidin,  is  found  in  the  orange  peel,  and  is  present  in  the  prepa- 
rations formed  directly  from  it,  while  it  is  absent  from  those  formed 
from  the  volatile  oil.  Ginger  contains  a  resin  of  hot,  burning  taste, 
which  increases  the  carminative  action  of  the  oil.  Cinnamon  contains 
some  tannic  acid,  which  passes  over  in  the  tincture,  while  a  fixed  oil 
is  contained  in  cardamom. 

Among  the  preparations  formed  from  the  crude  drugs  are  the 
Syrups,  which  are  used  exclusively  as  flavoring  agents. 

U.  S.  P. — Sijrupus  Aurantii  Florum,  Sjjr.  Ainygdalce,  Syr.  Aurantii,  Srjr. 
Rosa;,  Syr.  Zingiberis,  Syr.  Pruni  Virginiamv.    Dose,  4-16  c.c.  (1-4  fl.  drs.). 

B.  P. — Syrupus  Aromaticus  (containing  tincture  of  orange  and  cinnamon 
water),  Sijr.  Aurantii,  Syr.  Aura7itii  Floris,  Syr.  Limonis,  Sijr.  Priini  Virgini- 
ancB,  Syr.  Zingiberis.    Dose,  2-4  c.c.  (^-1  fl.  dr.). 

The  Tinctures  are  used  for  the  same  purposes  as  the  spirits  of  the 
pure  oils,  and  in  the  same  dose,  1-4  c.c.  (15-60  mins.). 

U.  S.  P. — Tmct.  Aurantii  Amari,  Tind.  Aurantii  Dulcis,  Tind.  Limonis 
Corticis,  Tmd.  Cardamomi  Composita  (containing  cardamom,  cinnamon,  car- 
away), Tind.  Cinnamomi,  Tind.  Lavand^ilct  Composita  (oils  of  lavender, 
rosemary,  cinnamon,  cloves,  nutmeg),   Tind.  Vanilla,   Tind.  Zingiberis. 

B.  V.~Tind.  Aurantii,  Tind.  Cardamomi  Composita  (containing  carda- 
mom, caraway,  cinnamon),  Tiiid.  Cinnamomi,  Tind.  Lavanduke  Composita 
(lavender,  rosemary,  cinnamon,  nutmeg),  Tind.  Limonis,  Tind.  Pruni  Vir- 
giniana;.  Tind.  Zingiberis. 

Fluid  Extracts  of  the  volatile  oil  series. 

U.  S.  P. — Fluidextradum  Aurantii  Arnari,  1  c.c.  (15  mins.). 

Fluidextradum  Pruni  Virginianw,  2  c.c.  (30  mins.). 

Fluidextractum  Zingiberis,  1  c.c.  (15  mins.). 

Fluidextradum  Aromaticum,  1  c.c.  (15  mins.),  from  aromatic  powder. 

Other  Preparations. 

Pubis  Aroinatirns  (U.  S.  P.)  contains  cinnamon,  cardamom,  ginger,  and 
nutmeg  in  powder,  and  is  a  useful  carminative  in  doses  of  1  G.  (15  grs.). 

Pnlris  Cinnamomi  Compositus  (B.  P.)  contain.s  cinnamon,  cardamom  and 
giiiiicr,  niul  is  used  as  a  carminative  in  closes  of  10  00  grs. 

Pure  Principles  used  as  flavors: 

Safrokun  (U.  S.  P.),  safrol  (C'6n3'('3H(.'C)()C,'lI:).  a  jiure  i)rincii)lc  found 
iu  sassafras  and  other  volatile  oils,  jjossesses  an  odor  Hk(^  sass:ifras.  It  is  a 
colorless  or  fainlly  yellow  liciuid,  s()Uil)le  in  alcohol  and  ether.  Dose,  0.3  c.c. 
(5  mins.). 


VOLATILE  OIL  SERIES  05 

Vanillinum  (U.  S.  P.),  vanillin  (CeHa-OH-OCHs'COH),  occurs  in  vanilla 
and  is  also  made  s.vnthetically.  It  forms  white  needle  cr_ystals,  slightly  soluble 
in  water,  easily  soluble  in  alcohol  and  ether,  and  possesses  the  odor  and  taste 
of  vanilla.    Dose,  0.03  G.  (|  gr.). 

Benzaldehydum  (U.  S.  P.),  benzaldehyde  (CeHsCOH),  occurs  in  the  oil  of 
bitter  almonds,  and  is  also  made  artificially.  It  is  a  colorless  fluid  with  the 
odor  and  taste  of  bitter  almond  oil,  very  slightly  soluble  in  water,  but  freely 
miscible  with  alcohol.     Dose,  0.03  c.c.  {\  min.). 

Eugenol  (U.  S.  P.),  a  phenol  (CeHsOH-OCHa-CsHs)  obtained  from  oil  of 
cloves  and  other  oils,  and  forming  a  colorless  liquid  with  an  odor  like  cloves, 
and  a  hot,  burning  taste.    Dose,  0.2  c.c.  (3  mins.). 

These  principles  are  used  exclusively  to  give  flavor  and  color. 

Bibliography. 

Bucholtz.    Arch.  f.  exp.  Path.  u.  Pharm.,  iv,  p.  1.     (Antiseptic  action.) 

Bokorny.    Arch.  f.  d.  ges.  Physiol.,  Ixxiii,  p.  555. 

Binz.    Arch.  f.  exp.  Path.  u.  Pharm.,  v,  p.  109;    viii,  p.  50. 

Pohl.     Ibid,  XXV,  p.  51. 

Brandt,  Scanzoni,  Farnsteiner.  Ztschr.  f.  Biol.,  xxix,  p.  277;  xxxiil,  pp.  462,  475. 
(Action  on  absorption  from  stomach  and  bowel;  compare  papers  by  Pawloiv  and  his 
pupils.     Arch,  des  Scienc.  biolog.,  ii  and  iii.) 

Heffter.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxv,  p.  342.     (Safrol,  etc.) 

Wintemitz.    Ibid.,  xlv,  p.  163. 

Fromm  u.  Hildebrandt.     Ztschr.  f.  physiol.  Chem.,  xxxiii,  p.  579;    xxxvi,  p.  441. 

Lindemann.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlii,  p.  356;    Ztschr.  f.  Biol.,  xxxix,  p.  1. 

Cuthbert  Hall.    Eucalyptus  Oils.     Thesis,  Sydney.  1904. 

Mattel.     Arch,  internat.  de  Pharmacodyn.,   14,  p.  331. 

Lapin.     Inaug.  Diss.,  Dorpat,  1893.     (01.  Menth.  pip.) 

Schwalb.     Arch.  f.  exp.   Path.,  Ixx,  p.  71. 

Macht.    Jour,  of  Pharm.,  iv,  p.  547. 

Cushny.    Proc.  Roy.  Soc.  Med.  Therap.,  Section  I,  p.  39.     (Nutmeg.) 

Dale.    Ibid.,  II,  p.  69.    (Nutmeg.) 

2.  Camphor. 

Some  of  the  volatile  oils  deposit  crystalline  substances  or  stearop- 
tenes  after  standing  for  some  time,  especially  when  they  are  exposed 
to  cold.  As  a  general  rule  these  bodies  are  present  in  only  small  amount, 
and  have  not  been  investigated  apart  from  the  volatile  oils,  of  which 
they  form  constituents;  but  a  few  of  them  have  attracted  attention 
in  therapeutics,  not  only  on  account  of  their  local  effects,  which  resemble 
those  elicited  by  the  volatile  oils  in  general,  but  also  because  of  their 
action  in  the  tissues  after  absorption.  The  chief  of  these  is  Camphor, 
which  has  been  used  in  Chinese  medicine  for  many  centuries,  and  which 
has  also  played  a  considerable  role  in  Western  therapeutics.  It  is 
derived  from  the  Cinnamomum  camphora  of  China  and  Japan,  and 
possesses  the  formula  CioHieO,  differing  from  the  terpenes  in  possessing 
a  ketone  (  =  C0)  link. 

Another  body  closely  resembling  ordinary  camphor  is  Borneol  or  Borneo- 
camphor  (CioHisO),  which  is  derived  from  the  Dryobalanops  aromatica,  and 
which  apparently  differs  from  ordinary  camphor  in  containing  the  group 
(  =  CHOH)  instead  of  (  =  C0).  Ngai-camphor,  which  is  obtained  from  Blumea 
balsamifcra,  is  very  closely  related  to  borneol.  Another  stearoptene  which 
has  been  used  in  medicine  apart  from  the  volatile  oils,  is  Menthol  (CioHsoO), 
which  is  obtained  from  the  oil  of  peppermint,  and  apparently  contains  u 
0 


66  SUBSTANCES  ACTING  LOCALLY 

CHOH  group  like  borneol,  but  is  more  completely  hydrated.  Borneol  has 
been  prepared  synthetically  from  camphor,  and  menthol  from  menthane, 
which  occurs  in  oil  of  peppermint.  Thujon,  an  isomer  of  camphor  occurring 
in  the  oil  of  wormwood  or  absinthe  and  in  many  other  plants,  has  not  been 
used  in  medicine,  but  is  of  great  importance  as  the  cause  of  epilepsy  in  chronic 
absinthe  drinkers. 

Symptoms. — Camphor  acts  as  an  irritant  to  the  skin  and  mucous 
membranes  like  the  volatile  oils,  and  has  a  hot,  bitter  taste,  and  induces 
in  small  quantities  a  feeling  of  warmth  and  comfort  in  the  stomach, 
while  after  large  doses  nausea  and  vomiting  may  be  caused  by  gastric 
irritation.  It  is  rapidly  absorbed  and  in  large  doses  induces  headache, 
a  feeling  of  warmth,  confusion,  and  excitement  in  man,  with  slowing 
of  the  pulse  and  flushing  of  the  skin.  This  excitement  may  be  shown  in 
hilarity  and  delirium  with  hallucinations,  in  restlessness,  or  in  sudden 
violent  movements,  which  pass  into  epileptiform  convulsions.  These 
alternate  with  pauses  of  quiet  and  unconsciousness,  which  become  longer 
until  the  patient  sinks  into  complete  stupor.  In  some  cases  of  poisoning 
no  excitement  is  observed,  the  patient  falling  into  a  condition  of  drowsi- 
ness, unconsciousness  and  stupor  immediately.  In  the  lower  mammals, 
camphor  induces  very  similar  symptoms,  wild  excitement  and  epilepti- 
form convulsions,  followed  by  depression,  stupor,  collapse,  and  death 
from  failure  of  the  respiration.  Not  infrequently,  however,  the  respira- 
tion ceases  during  a  convulsion  and  fails  to  return  when  it  passes  oflF. 

In  the  frog  no  excitement  is  observed  except  from  the  local  irri- 
tation; the  animal  falls  into  a  condition  of  depression,  in  which  no 
spontaneous  movements  are  made,  although  the  reflexes  seem  to  be 
little  affected  at  first.  Later,  the  refiexes  disappear  and  the  animal  lies 
completely  paralyzed. 

Action:  Central  Nervous  System. — In  the  frog  camphor  depresses  the 
brain  and  later  the  spinal  cord,  so  that  the  action  is  a  descending 
paralysis  similar  to  that  seen  under  chloroform  and  other  aiuesthetics; 
thujon  often  induces  violent  spasms,  which  appear  to  arise  from  stimula- 
tion of  the  spinal  cord  and  medulla  oblongata. 

The  convulsions  in  mammals  are  certainly  not  due  to  any  action 
on  the  spinal  cord,  but  to  stinmlation  of  the  higher  areas  of  the 
nervous  axis.  The  cerebral  cortex  is  involved  in  the  action,  for  the 
convulsions  are  less  marked  on  its  removal;  but  in  the  lower  mammals 
the  chief  action  seems  to  be  exerted  on  the  nervous  centres  situated 
between  the  cerebral  peduncles  and  the  medulla  oblongata.  It  is  not 
imj)robal)le  that  in  man  the  cerebral  aetion  may  be  more  marked  than 
that  on  tiie  lower  areas,  for  on  descending  lower  in  the  scale  it  is  foimd 
that  the  cerebral  action  becomes  less  evident;  thus  in  birds  the  removal 
of  the  cerebrum  seems  to  have  no  effect  on  the  convulsions.  The  loss 
of  consciousness  and  the  stupor  ol)serve(l  in  man  and  the  higher  animals 
point  to  a  final  i)aralysis  of  the  cerebral  cortex.  Later  the  spinal  cord 
and  the  medulla  are  paralyzed  and  resjuration  ceases;  some  observers 
state  that  the  reflexes  of  the  spinal  cord  are  first  augmented  by  large 
do.ses  of  camphor  but  others  describe  de])ression  as  the  first  result. 


VOLATILE  OIL  SERIES 


67 


The  Terminations  of  the  Motor  Nerves  are  paralyzed  in  tlie  frog  by 
large  doses  of  camphor,  but  not  in  mammals.  The  Muscles  are  weak- 
ened and  paralyzed  when  the}'  are  directly  exposed  to  its  solutions  or 
vapor. 

The  Heart  is  sometimes  slowed  by  camphor  and  its  allies  in  man 
and  animals,  but  is  generally  little  affected  in  either  strength  or  rate. 
It  has  been  stated  that  the  heart  has  less  tendency  to  pass  into  fibrilla- 
tion under  camphor,  but  this  is  not  confirmed.  Similarly,  camphor 
has  been  credited  with  dilating  the  coronary  vessels  and  thus  promoting 
the  nutrition  of  the  heart,  but  according  to  Meyer  this  occurs  only 
under  poisonous  quantities  and  is  therefore  devoid  of  therapeutic 
interest.  In  the  frog  camphor  appears  to  have  some  stimulant  action 
on  the  heart  muscle  when  directly  applied  to  it,  but  in  mammals  its 
effects  on  the  heart  in  therapeutically  possible  amounts  are  trifling  or 
entirely  negative. 

In  mammals,  camphor  reduces  the  blood-pressure,  though  there  is 
sometimes  a  transient  rise  at  first.  The  fall  in  pressure  appears  to  be 
due  to  dilatation  of  the  peripheral  vessels;  the  pulmonary  vessels 
share  in  this  dilator  action.  It  is  not  quite  clear  whether  this  action 
is  exercised  directly  on  the  vessel  walls  or  centrally,  but  the  former  is 
the  more  probable  view.  When  sufficient  camphor  is  given  to  cause 
convulsions,  great  variations  in  the  blood-pressure  occur,  a  very  marked 
rise  being  observed  during  the  convulsive  attacks,  while  in  the  interval 
it  falls  to  below  the  normal  height;  these  variations  appear  to  arise 
from  a  direct  action  on  the  vasomotor  centre,  which  partakes  in  the 
general  stimulation.  The  peripheral  vessels  have  been  found  to  be 
dilated  by  camphor  solutions  perfused  through  them,  and  this  action 
may  explain  the  slight  fall  in  pressure  often  seen  after  absorption  of 
the  drug.  This  slight  dilation  of  the  vessels  is  the  only  change  in  the 
circulation  observed  after  camphor,  unless  when  quantities  sufficient 
to  cause  convulsions  are  injected. 

The  Respiration  is  somewhat  slower  and  deeper  than  normal,  but 
this  alteration  is  generally  insignificant.  During  the  convulsions  it 
is  arrested,  while  in  the  intervals  it  may  be  accelerated  from  the 
muscular  exertion  during  the  spasms. 

The  normal  Temperature  is  not  affected  by  camphor,  but  in  fever 
it  acts  as  an  antipyretic,  like  many  other  aromatic  bodies. 

Camphor  is  partially  oxidized  in  the  tissues,  forming  camphorol 
(C10II16O2),  which  is  Excreted  in  the  urine  in  combination  with  glycu- 
ronic  acid,  as  a-  and  ^^-camphoglycuronic  acid,  and  also  in  part  in 
combination  with  a  nitrogenous  body,  which  is  probably  uramidogly- 
curonic  acid.  Camphorol  acts  like  camphor,  but  its  glycuronic  acid 
combinations  are  inactive,  so  that  the  effects  of  camphor  pass  off 
quickly  in  such  animals  as  the  dog,  in  which  these  combinations  are 
rapidly  formed. 

Camphor  is  possessed  of  some  antiseptic  action,  although  it  is  much 
weaker  than  some  of  the  bodies  of  the  carbolic  acid  group,  and  also 
than  many  of  the  volatile  oils.     Leucocytes  cease  their  mo\'ements 


68  SUBSTANCES  ACTING  LOCALLY 

at  once  when  exposed  to  camphor  sokitions  or  vapor,  and  Darwin 
found  that  it  acts  as  a  stimukis  to  the  tentacles  of  Drosera,  an  insectiv- 
orous i)Iant,  and  apparently  renders  them  more  sensitive  to  mechanical 
irritation. 

Camphor  produces  redness  and  a  feeling  of  warmth  when  rubbed 
into  the  Skin.  Sometimes,  however,  a  distinct  sensation  of  cold  may 
be  experienced,  providing  the  rubbing  is  not  too  energetic.  ^Menthol 
generally  induces  this  feeling  of  cold,  accompanied  by  more  or  less 
prickling,  and  afterward  by  heat  and  burning.  The  cold  is  not  due 
to  cooling  of  the  skin,  for  the  vessels  of  the  part  are  dilated,  and  the 
thermometer  indicates  a  higher  skin  temperature  there  than  in  other 
parts  of  the  body.  It  has  been  ascribed  to  menthol  being  more  irritant 
to  the  terminations  of  certain  nerves  which  con\'ey  the  sensation  of 
cold  than  to  those  of  the  heat  nerves  and  pain  nerves,  but  this  is  denied 
by  Hollett  who  states  that  menthol  acts  only  on  the  terminations  of 
the  nerves  of  common  sensation  or  pain.  A  feeling  of  numbness  and 
partial  anaesthesia  follows  its  application  after  some  time,  and  a  10  per 
cent,  solution  has  been  found  to  produce  anaesthesia  of  the  cornea, 
which,  however,  is  preceded  by  pain  and  smarting. 

The  action  of  borneol,  menthol,  bromated  camphor,  and  camphorol  is 
almost  identical  with  that  of  camphor  itself.  Borneol  is  less  irritant  locally, 
and  the  convulsions  are  less  severe  than  after  camphor,  so  that  animals  seldom 
die  during  the  convulsive  stage,  and  may  remain  in  a  state  of  stupor  and  col- 
lapse for  one  or  two  days  before  the  respiration  finally  ceases.  After  menthol, 
the  convulsions  are  even  less  developed  than  after  borneol.  Both  of  these  are 
excreted  in  combination  with  glycuronic  acid.  Bromated  camphor  seems  to 
resemble  borneol  more  closely  than  camphor  or  menthol,  while  amido-cam- 
phor  produces  symptoms  similar  to  those  of  camphor,  but  is  much  less  powerful. 
Natural  camphor  is  dextrorotary;  the  lasvorotary  isomer  has  been  formed 
recently,  and  is  found  to  resemble  the  natural  form  except  in  being  rather  more 
toxic. 

Preparations. 

Camphora  (U.  8.  P.,  B.  P.)  (CioHieO),  Laurel  camjihor,  a  stearoptene  ob- 
tained from  Cinuamomum  Camphora,  forms  white  translucent,  crystalline 
masses,  which  are  almost  insoluble  in  water  but  dissohe  readily  in  alcohol, 
ether,  chloroform,  fixed  and  volatile  oils.  0.125  G.  (2  grs.),  in  emulsion  or 
pill  (B.  P.,  2-5  grs.). 

Aqua  Camphora;  (U.  S.  P.,  B.  P.). 

Si'iHiTus  Camphor.e  (U.  S.  p.,  h.  p.),  1  c.c.  (15  mins.).     B.  P.,  5-20  mins. 

Li.viMENTUM  Camphor.e,  Camphorated  oil  (U.  S.  P.,  B.  P.). 

Linimentum  CamphorcE  Amnioniatum  (B.  P.),  compound  camphor  liniment. 

TiNCTUUA  Camphor.ii:  Composita  (B.  p.),  paregoric,  contains  1  part  of 
morphine  in  2000,  i.  e.,  each  fluid  drachm  is  equivalent  to  \  grain  of  opium. 
i-Ul.dr. 

Camphor  is  also  an  ingredient  in  the  camphorated  tincture  of  ()i)iuin,  or 
paregoric  (U.  S.  P.)  and  in  soap  liniment  and  chloroform  liniment. 

Menthol  {V.  S.  P.,  B.  1'.)  (CioHjuO),  a  stearoptene  obtained  from  the  oil  of 
p  'ppei mint,  consists  of  colorless  crystals  slightly  soluble  in  water,  freely  soluble 
in  alcohol  or  el  her. 

Therapeutic  Uses.  (  ani|)li()r  is  u.sed  (.'xternaliy  in  the  I'orni  of  the 
liniment  or  spirit  as  a  nuld   rubefacient  in  brni.ses  and  sprains,  and 


VOLATILE  OIL  SERIES  69 

also  to  destroy  parasites.  Internally  the  spirit  is  prescril)e(l  as  a 
carminative  and  as  an  intestinal  disinfectant.  It  is  frequently  given 
to  prevent  "chill,"  and  may  relieve  the  congestion  of  internal  organs 
through  dilating  the  skin  vessels. 

There  is  no  reason  to  believe  that  camphor  in  even  the  largest  thera- 
peutic doses  has  any  effect  after  absorption  except  a  slight  dilatation 
of  the  skin  vessels,  and  it  is  possible  that  this  also  may  arise  from  its 
gastric  eflfects.  Its  former  uses  in  hysteria,  epilepsy  and  other  nervous 
disorders,  as  an  aphrodisiac  and  as  an  anaphrodisiac  were  all  equally 
irrational;  if  any  improvement  occurred,  it  was  due  to  hypnotic 
suggestion  and  not  to  the  action  of  the  drug. 

It  has  been  used  in  unconsciousness  and  collapse  arising  from  different 
causes,  and  in  the  depression  and  weakness  of  acute  fevers.  In  many 
of  these  cases,  a  marked  improvement  in  the  pulse  is  said  to  have  been 
observed;  this,  like  the  similar  improvement  seen  after  alcohol,  may 
perhaps  be  explained  by  its  action  as  a  local  stomachic  irritant  produc- 
ing changes  in  the  circulation  reflexly.  Solutions  of  camphor  have 
been  injected  subcutaneously  in  these  cases,  but  they  cause  pain  and 
swelling  at  the  point  of  injection. 

Camphor  is  often  prescribed  in  expectorant  mixtures,  especially 
in  combination  with  opium,  as  in  paregoric. 

Menthol  is  used  almost  exclusively  for  its  effects  on  the  sensory 
nerve  terminations,  and  is  applied  by  rubbing  the  crystals  or  sticks 
on  the  skin  in  case  of  headache  and  neuralgia. 

Borneol  and  monobromated  camphor  are  entirely  superfluous.  The  latter 
was  at  one  time  used  as  a  sedative  in  nervous  excitement,  but  does  not  seem 
to  have  been  at  all  beneficial  and  has  fallen  into  disuse. 

Bibliography. 

Rovighi.     Zts.  f.  phys.  Chem.,  xvi,  p.  20. 

Schmiedeberg  u.  Meyer.    Ibid.,  iii,  p.  422. 

Stockman.    Journ.  of  Physiol.,  ix,  p.  65. 

Leivin.    Arch.  f.  exp.  Path.  u.  Pharm.,  xxvii,  p.  226. 

Gottlieb.    Ibid.,  xxx,  p.  31.     Ztschr.  f.  exp.  Path.  u.  Ther.,  ii,  p.  385. 

Meyer.    Arch.  f.  exp.  Path.  u.  Pharm.,  xxix,  p.  438. 

Wiedemann.    Ibid.,  vi,  p.  216. 

Goldscheider.    Arch.  f.  Anat.  u.  Phys.,  1886,  p.  555. 

Rolletl.    Pfliiger's  Archiv,  Ixxiv,  p.  418. 

Seligmann,  Boehme.    Arch.  f.  exp.  Path.  u.  Pharm.,  Hi,  pp.  333,  346. 

Winterberg.     Pfluger's  Archiv,  xciv,  p.  455;  Ztschr.  f.  exp.  Path.  u.  Ther.,  iii.  p.  182. 

Magnan.    Compt.  rend,  de  I'Acad.,  Ixviii,  p.  825.    (Absinth.) 

Hildebrandt.    Arch.  f.  exp.  Path.  u.  Pharm.,  xlviii,  p.  451.    (Thujon.) 

Liebmann.     Ibid.,  Ixviii,  p.  59. 

3.  Ether  and  Chloroform  (Local  Action). 

In  addition  to  their  use  as  anaesthetics,  chloroform  and  ether  are 
sometimes  prescribed  for  the  same  purposes  as  the  volatile  oils. 
Chloroform  has  a  hot,  sweetish  taste,  while  ether  is  bitter  and  suffo- 
cating in  the  mouth;  a  sensation  of  heat  and  often  of  pain  in  the 
stomach  follows  when  they  are  swallowed,  and  chloroform  mav  cause 


70  SUBSTANCES  ACTING  LOCALLY 

gastric  irritation  and  catarrli  when  <jiven  undilutcfl.  When  ether  has 
been  exposed  to  air  and  sunlight  and  to  a  varying  tenii)erature,  it  may 
contain  acetaldehyde  and  peroxiiU'  hodies,  wliich  render  it  more  irritant 
to  the  mucous  membranes.  The  wliole  ett'ect  is  similar  to  that  produced 
by  the  volatile  oils,  but  absorption  probably  takes  place  more  rapidly. 
On  the  skin,  ether  evaporates  too  rapidly  to  cause  much  irritation, 
but  chloroform  is  occasionally  used  as  a  rubefacient  in  the  form  of  a 
liniment. 

Preparations. 

The  pure  substances  may  be  administered  by  the  moutli,  but  more  frequentlj^ 
other  preparations  are  prescribed. 

Chloroform,  0.3  c.c.  (5  mins.). 

Mther,  1  c.c.  (15  mins.). 

Spiritus  iETHERis  (U.  S.  P.,  B.  p.),  4  c.c.  (1  fl.  dr.).     B.  P.  20-40  mins. 

Spiritus  JilTHERis  CoMPOSiTUS  (U.  S.  P.),  (Hoffmann's  Anodjaie)  contains 
a  number  of  esters  of  ethyl  and  other  substances  known  as  "ethereal  oil," 
together  with  ether  and  alcohol,  4  c.c.  (1  fl.  dr.). 

Spiritus  Chloroformi  (U.  S.  P.,  B.  P.),  2  c.c.  (30  mins.)  (5-20  m.  for  re- 
peated doses,  B.  P.). 

Aqua  Chloroformi  (U.  S.  P.,  B.  P.). 

Linimentum  Chloroformi  (U.  S.  P.,  B.  P.). 

Therapeutic  Uses. — These  preparations  are  used  for  the  same  pur- 
poses as  the  corresponding  preparations  of  the  volatile  oils.  Thus  the 
spirits  may  be  prescribed  as  carminatives  or  in  colic,  while  the  liniment 
is  used  as  a  counter-irritant.  Chloroform  water  is  an  antiseptic  of 
considerable  power,  but  is  too  volatile  for  surgical  use. 

Spirits  of  ether  and  ether  itself  are  often  given  internally  or  sub- 
cutaneously  in  cases  of  shock  or  sudden  collapse  in  the  same  way  as 
brandy  or  whiskey,  though  Elfstrand  states  that  ether  injected  hypo- 
dermically  has  no  effect  on  the  heart  or  blood-pressure;  spirits  of 
ether  contains  a  much  larger  percentage  of  alcohol  than  ordinary 
whiskey.  Both  ether  and  chloroform,  but  more  especially  the  latter, 
have  been  used  internally  for  tapeworm  with  success.  There  is  always 
some  danger,  however,  that,  besides  destroying  the  parasite,  they  may 
cause  irritation  and  lasting  injury  to  the  intestinal  wall. 

Iloll'mann's  anodyne  is  a  favorite  carminative,  and  is  often  added  to 
other  drugs  to  lend  them  an  agreeable  odor  and  taste.  It  is  also  used 
in  dilution  as  a  stimulant  in  the  same  indefinite  way  as  wine  and  spirits, 
and  its  large  |)ercentage  of  alcohol,  together  with  the  bouquet  given 
it  by  the  \'arious  esters  present,  entitle  it  to  be  ranked  among  the 
alcoholic  preparations. 

Both  spirits  of  ether  are  used  occasionally  in  expectorant  mixtures 
and  are  believed  to  increase  the  bronchial  secretion. 

Ether  evaporates  \ery  rapidly  and  leaves  a  sensation  of  cold,  and 
when  thrown  on  the  skin  in  a  fine  spray  it  produces  sufficient  cold 
to  numb  sensation  in  tlie  part  and  allow  of  minor  surgical  operations 
(see  uses  of  cocaine).  Instead  of  ether  still  more  volatile  substances, 
such  as  ethyl  chloride  (boiling  point  12.5°  C),  methyl  chloride  (boiling     | 


VOLATILE  OIL  SERIES  71 

point  —  2o°  C.)  and  liquefied  carbon  dioxide  have  been  introduced. 
These  are  sui)phed  in  pressure  cyhnders,  and  are  allowed  to  escape 
against  the  skin. 

The  local  anaesthesia  produced  bears  no  relation  to  their  action  when 
inhaled,  but  is  due  simply  to  the  cold  produced  by  their  evaporation. 
The  vessels  of  the  part  contract,  and  the  absence  of  blood  and  hardness 
of  the  tissues  facilitate  some  operations,  but  the  subsequent  reaction 
is  liable  to  produce  considerable  soakage  of  blood  from  the  wound. 
The  cold  elicited  ought  not  to  be  great  enough  to  actually  freeze  the 
tissues,  otherwise  the  healing  may  be  slow.  The  intense  cold  is  often 
quite  as  painful  as  the  operation  itself  would  be  without  any  anaesthetic. 

4.  Malodorous  Volatile  Oils. 

Some  of  the  volatile  oils  differ  from  the  others  in  possessing  an  odor 
which  is  disagreeable  and  nauseating  to  most  people,  although  not  to 
all.  The  best  known  of  these  are  the  Oils  of  Asafostida  and  Valerian. 
The  former  occurs  along  with  resins  and  gums  exuding  from  some 
species  of  Ferula,  and  contains  several  organic  sulphur  compounds,  to 
which  it  owes  its  odor.  Oil  of  Valerian,  from  Valeriana  officinalis,  is 
almost  without  odor  when  freshly  distilled,  but  when  kept  for  some 
time  and  exposed  to  the  air,  it  assumes  a  somewhat  unpleasant  pene- 
trating odor.  It  contains  two  terpenes,  borneo-camphor,  and  numerous 
esters  of  formic,  acetic  and  valerianic  acid.  While  both  of  these  oils 
are  generally  regarded  as  possessing  very  unpleasant  odors,  asafoetida 
is  used  in  India  as  a  condiment,  and  valerian  was  formerly  used  in 
England  as  a  perfume.  Another  drug  of  the  same  kind  formerly  in 
use  is  Sumbul,  the  root  of  Ferula  Sumbul. 

Asafoetida  and  valerian  are  used  in  hysterial  affections,  and  the 
benefits  accruing  from  their  administration  have  generally  been 
attributed  to  the  mental  impression  produced  by  their  unpleasant 
odor  and  taste,  and  not  to  any  action  they  produce  after  absorption. ^ 

The  ordinary  valerianic  salts  have  no  further  effects  than  other 
salts  of  the  acetic  acid  series,  so  that  it  is  quite  irrational  to  use  such 
bodies  as  valerianate  of  quinine  for  their  action  in  hysteria. 

Asafoetida  is  also  used  like  the  other  volatile  oils  as  a  carminative 
and  as  an  expectorant,  and  the  emulsion  is  given  by  the  mouth  or  in 
an  enema  to  relieve  abdominal  distention. 

Preparations. 

Asafoetida  (U.  S.  P.),  a  mixture  of  volatile  oil,  gum,  and  resin  from  Ferula 
fcEtida.     0.25  G.  (4  grs.) 

Emulsum  Asafoetidce,  16  c.c.  (4  fl.  drs.). 

Pilulce  Asafoetidce,  2  pills. 

Tindura  Asafoetidce,  1  c.c.  (15  mins.). 

'  Kionka  (Arch,  internat.  de  Pharmacodyn.,  xiii,  p.  215)  ascribes  the  effect  of  valerian 
to  a  definite  action  on  the  psychical  functions  and  the  circulation  exercised  by  some 
valerianic  esters  of  the  oil,  and  has  recommended  some  artificial  esters  (Valyl)  as  a 
substitute  for  the  valerian  preparations;  but  his  statement  requires  further  confirmation. 


72  SUBSTANCES  ACTING  LOCALLY 

Asafetida  (B.  P.),  a  fruin-rcsin  obtained  from  the  root  of  Ferula  fd'tida  and 
prol)al)ly  other  species.     5-15  grs. 

Tiudura  Asafctukc,  ^-1  fl.  dr. 

Pilulci  Alue.s  el  Asnfctidce,  4-S  grs. 

Spiritus  Ammonia;  Fetidus,  20-40  mins.  for  repeated  administration;  for  a 
single  administration  60-90  mins. 

Valeriana  (U.  S.  P.),  Valerianae  Rhizoma  (B.  P.),  valerian,  the  rhizome  and 
roots  of  Valeriana  officinalis. 

Fluidextradum  Valeriance  (U.  S.  P.),  2  c.c.  (30  mins.). 

Tindum  Valericmce  (U.  S.  P.),  4  c.c.  (1  fl.  dr.). 

Tindura  Valerianae  Ammoniata  (U.  S.  P.,  B.  P.),  2  c.c.  (30  mms.).  B.  P., 
1-1  fl.  dr. 

VII.    SKIN  IRRITANTS  AND  COUNTER  IRRITATION. 

Tlie  practice  of  applying  irritants  to  the  skin  in  internal  diseases 
is  one  of  great  antiquity.  The  theories  on  which  this  therapeutic 
method  is  based  have  changed  with  the  advance  of  medical  knowledge, 
until,  no  explanation  satisfactory  to  modern  scepticism  being  forth- 
coming, the  use  of  these  remedies  has  fallen  into  a  certain  disrepute 
in  the  last  few  years.  The  old  theory  of  revulsion  or  derivation  was  at 
first  based  on  the  belief  that  disease  was  a  malignant  entity  or  humor, 
which  might  be  drawn  from  the  deeper  organs  to  the  surface  by  means 
of  irritation  of  the  skin.  Later,  it  was  supposed  that  the  congestion  of 
the  diseased  organs  might  be  relieved  by  the  withdrawal  of  fluid  to 
the  skin,  and  this  belief  has  been  held  in  more  or  less  modified  forms  in 
quite  modern  times.  In  addition,  it  was  recognized  very  early  that 
irritation  of  the  skin  relieved  pain  in  many  instances.  The  means  by 
which  the  skin  irritation  was  attained  were  extremely  numerous  and 
varied;  large  numbers  of  drugs  have  been  used,  and  in  addition  mechan- 
ical devices  of  all  kinds  were  employed,  such  as  burning,  electrical 
currents,  or  the  introduction  of  setons.  In  many  of  these  the  idea  of 
irritation  was  combinetl  with  that  of  leaving  a  way  of  escape  for  humors. 
This  latter  is  only  of  historical  interest,  but  the  practice  of  relieving 
internal  organs  by  external  irritation  or  coimter-irrifation  persists  still, 
and  perhajjs  merits  more  attention  than  it  receives  at  the  hands  of 
many  physicians. 

The  efiects  of  an  irritant  applied  to  the  skin  are  local  and  remote. 
The  first  symptoms  of  irritation  are  congestion  and  redness  of  the 
part,  and  many  drugs  which  produce  only  this  degree  of  irritation  in 
ordinary  circumstances,  are  known  as  Hubrfncicnts.  Stronger  irritants 
cause  blistering,  and  are  called  J'csicaiifs,  while  some  drugs  which 
cause  irritation  and  small  discrete  suppurations,  receive  the  name  of 
Pusiulants. 

Local  Symptoms.  The  api)lication  of  an  irritant  to  the  skin  causes 
a  IVcling  of  warnith,  and  often  of  itching,  which  may  later  become 
intensified  into  actual  i)ain.  The  skin  becomes  red,  congested,  warm, 
and  at  first  is  more  sensitive  to  touch  and  painful  stunuli,  though 
the  sensitiveness  is  afterward  lessened.  This  condition  persists  for 
a  longer  or  shorter  time  aeeonliiig  to  the  nature  of  the  irritant,  and 


SKIN  IRRITANTS  AND  COUNTER-IRRITATION  73 

then  passes  off  slowly.  Very  often  desquamation  follows,  if  the  rube- 
facient has  acted  for  some  length  of  time.  Stronger  irritation  is  followed 
at  first  by  the  same  results,  but  soon  small  globules  of  fluid  appear 
below  the  ei)iderniis,  and  these  coalesce  so  as  to  form  a  large;  accumula- 
tion of  fluid,  which  raises  the  epidermis  completely  oft'  the  true  skin, 
forming  a  blister.  If  the  irritant  be  removed,  the  fluid  of  the  blister 
undergoes  a  slow  absorption,  so  that  in  the  course  of  a  few  days  the 
epidermis  forms  an  empty  sack,  which,  however,  is  not  obliterated  by 
the  adhesion  of  the  walls.  If  the  blister  be  opened,  the  sensitive  dermis 
is  exposed,  and  the  secretion  of  fluid  continues  for  some  time,  until  a  new 
epidermis  has  been  formed. 

The  distinct  and  separate  points  of  inflammation  caused  by  the 
pustulants  are  due  to  their  affecting  the  orifices  of  the  skin  glands 
and  not  intervening  tissue.  This  has  been  ascribed  in  some  instances 
to  the  drug  being  rendered  irritant  at  these  points  by  the  presence 
of  acids  formed  by  the  decomposition  of  the  sebum  and  perspiration; 
a  simpler  explanation  is  that  the  pustulants  cannot  pass  through  the 
horny  epidermis,  but  act  as  irritants  wherever  they  come  in  contact 
with  living  tissue,  that  is,  at  the  orifices  of  the  glands.  They  cause  the 
same  sensation  of  warmth  and  prickling  of  the  skin  as  the  other  irritants, 
but  even  in  the  earlier  stages  of  their  action  small,  dark-red,  raised 
points  are  observed,  exactly  as  in  some  of  the  exanthemata,  and  these 
afterward  form  small  abscesses.  If  the  application  be  persisted  in, 
these  discrete  abscesses  may  burst  through  the  intervening  tissues  and 
become  confluent,  and  large  abscesses  have  thus  been  formed  in  the 
skin.  When  the  irritant  is  removed  before  the  formation  of  pus,  the 
inflammation  of  the  ducts  slowly  subsides  and  the  epidermis  peels  off 
as  after  the  milder  irritants.  Pustulants  are  seldom  employed  at  the 
present  time;  croton  oil  applied  vigorously  may  induce  pustulation, 
a-nd  tartar  emetic  was  formerly  largely  used  for  this  purpose. 

The  local  effects  of  the  rubefacients  and  vesicants  are  identical 
with  those  of  acute  inflammation.  The  pain  and  discomfort  are  due 
to  the  action  on  the  nerve  terminations,  while  the  redness  and  swelling 
betray  the  local  dilatation  of  the  vessels.  This  latter  appears  to  be 
due  to  a  reflex  from  the  sensory  terminations  to  the  vasodilator  nerve 
ends  on  the  vessels;  the  central  nervous  system  is  not  involved  in  this 
reflex,  for  it  occurs  after  division  of  the  nerves  of  the  part,  but  not 
after  the  peripheral  flbres  have  degenerated;  it  is  thus  of  the  nature  of 
an  axon  reflex  (Bruce).  The  dilatation  of  the  vessels  and  the  slowing 
of  the  blood  current  in  them  lead  to  the  transudation  of  fluid  and 
leucocytes  into  the  tissues,  especially  at  the  points  where  the  irritation 
is  greatest,  and  the  accumulation  eventually  pushes  off  the  horny 
epidermal  layer  from  the  living  layers  and  forms  a  blister.  The  fluid 
in  the  blister  has  been  show^n  to  contain  some  of  the  irritant,  which 
diffuses  into  it  through  the  epidermis.  The  oedema  and  swelling  is  not 
confined  to  the  skin,  but  extends  into  the  subcutaneous  tissue  and  the 
more  superficial  layers  of  muscle. 


74  SUBSTANCES  ACTING  LOCALLY 

If  the  irritation  be  continued  long  enough,  suppuration  may  com- 
mence in  the  bhster  and  lead  to  deep  erosion  of  the  tissues. 

Remote  Action. — Local  irritation  cannot  exist  without  causing 
certain  general  changes  which  afi'ect  the  whole  organism,  and  which 
arise  from  the  reflex  stimulation  of  various  centres  in  the  medulla 
oblongata.  Attempts  to  base  the  explanation  of  counter-irritation 
on  these  general  effects  have  all  failed,  however,  and  many  of  them 
are  elicited  only  by  widespread  irritation  or  by  more  intense  localized 
irritation  than  is  induced  by  ordinary  therapeutic  methods. 


Fig.  1 


Diagram  to  illustrate  the  effects  of  visceral  disease  on  sensation  (after  Mackenzie) 
S,  diseased  viscus,  with  afferent  nerve  fibre  N  and  efferent  fibre  A^'  issuing  from  the 
same  area  of  the  spinal  cord.  The  impulses  from  the  diseased  area  induce  a  condition  of 
heightened  sensibility  in  the  shaded  area.  E,  a  motor  nerve  fibre  to  muscle,  which 
carries  more  impulses  than  usual  from  the  area  in  the  cord  and  thus  leads  to  a  tonic 
contraction  of  the  muscle.  A,  the  afferent  nerve  from  the  muscle  and  A'  from  the  skin 
entering  the  cord  in  the  sensitive  area  and  thus  giving  rise  to  the  sense  of  pain  and  tender- 
ness, which  is  referred  to  the  peripheral  distribution  in  the  skin  and  muscle. 


The  contrcs  involved  arc  those  regulating  the  heart,  the  tone  of  the  vessels, 
and  the  respiration.  Moderate  irritation  of  the  skin  causes  an  acceleration  of 
the  heart-rhj'thm,  wlul(>  more  iiowerful  irritation  slows  the  heart  through  the 
inhibit(jry  centre.  The  blood-pressure  measured  in  the  arteries  is  consiilerably 
increased  by  ordinary  irritation  of  the  skin,  but  if  it  be  very  severe  or  wide- 
spread, the  slowness  of  the  pulse  niaj'  cause  a  fall  of  tension.  This  increase  in 
the  blood-pressure  is  due  to  the  reflex  stinuilation  of  the  vasomotor  centre, 
wliich  causes  a  constriction  of  the  arterioles  of  the  abdominal  organs  chiefly, 
while  the  vessels  of  the  limbs  and  ])robal)ly  those  of  the  skin  are  not  contracted. 
The  result  is  that  more  blood  is  suj)plie(i  to  the  muscles  and  skin  and  less  to 
the  internal  organs  than  normally. 

The  effects  of  skin  irritation  on  the  respiration  are  less  uniform.  In  the 
rabbit  the  breathing  is  sometimes  accelerated,  sometimes  slowed  by  mild 
stinmlation,  while  stronger  stinudi  seem  to  slow  it  always.     The  effect  of  the 


SKIN  IRRITANTS  AND  COUNTER-IRRITATION  75 

ai)i)licati()u  of  skin  irritants  on  tlie  respiration  in  man  has  not  been  ol)servcd 
a(u;urately,  bnt  that  sudden  stinudation  of  the  skin  causes  gasping  and  irrcguhir- 
ity  of  the  respiration,  may  l)e  observed  whenever  cold  water  coni(!S  in  contact 
with  the  more  sensitive  parts  of  the  body. 

Some  cliange  in  the  temperature  of  the  body  has  been  observed  when  the  skin 
is  irritated,  but  in  man  tliis  is  said  to  amount  to  less  than  0. 1°  C.  as  a  general  rule. 
The  internal  heat  tends  to  fall,  while  that  of  the  skin  rises,  from  the  change  in  the 
distribution  of  the  blood  which  has  been  described  above. 

The  metabolism  has  been  found  to  be  altered  by  the  application  of  irritants 
to  the  skin,  and,  although  in  the  experiments  on  which  this  statement  is  based, 
the  surface  exposed  to  the  irritant  was  larger  than  that  affected  in  therapeutics, 
it  seems  probable  that  some  change  is  produced  by  the  ordinary  agents  also. 
Zuntz  and  Rohrig  found  that  bathing  animals  in  strong  salt  solution  increased 
the  oxygen  absorbed  and  the  carbonic  acid  excreted  much  more  than  bathing 
in  ordinary  water,  and  Paalzow  obtained  the  same  result  from  the  application  of 
mustard  plaster.  The  nitrogen  of  the  urine  is  also  said  to  be  increased.  This 
increase  in  the  oxidation  of  the  tissues  is  of  the  same  nature  as  that  produced 
by  cold,  and  is  due  to  an  augmentation  of  the  muscular  activity,  which,  however, 
is  too  slight  to  cause  any  perceptible  movement. 

Irritation  of  the  skin  induces  leucocytosis  in  the  same  way  as  irritation 
of  the  alimentary  canal.  This  is  especially  evident  after  the  application  of 
a  vesicant  such  as  cantharides  plaster,  while  rubefaction  seems  to  have  less 
effect. 

Lastly,  in  considering  the  effects  of  skin  irritation  on  the  general  vitality,  it 
may  be  mentioned  that  a  sudden  application  may  awake  the  consciousness,  as 
is  seen  in  the  effects  of  dashing  cold  water  on  the  chest,  or  of  striking  the  hands 
ill  narcotic  poisoning.  Another  example  is  seen  in  the  improved  mental  con- 
dition so  often  observed  in  fever  patients  treated  with  cold  baths.  This  im- 
provement is  due  to  the  local  action  on  the  skin,  and  not,  as  is  often  said,  to 
the  fall  in  temperature,  for  the  latter  is  often  insignificant. 

All  of  these  effects  are  produced  by  irritation  at  any  point  of  the 
surface,  and  are  quite  insufficient  to  explain  the  practical  use  of  counter- 
irritants  to  affect  a  particular  organ.  For  example,  in  gastric  disorders 
a  counter-irritant  is  often  applied  just  over  the  ensiform  cartilage, 
while  in  facial  neuralgia  a  blister  behind  the  ear  often  gives  relief. 
If  the  beneficial  results  were  due  to  the  general  alteration  of  the  circula- 
tion, respiration,  or  temperature,  there  would  be  no  reason  to  vary 
the  point  of  application,  for  the  effect  would  not  vary. 

It  has  been  shown  by  several  observers  (Zuelzer,  Lazarus-Barlow) 
that  when  an  irritant  is  applied  to  the  skin,  the  muscles  beneath  are 
congested  and  rich  in  lymph,  and  Erlanger  states  that  solutions  are 
absorbed  more  quickly  from  the  pleural  cavity  when  mustard  is  applied 
to  the  skin  of  the  chest  and  attributes  this  to  an  acceleration  of  the 
lymph  stream.  But  these  observations  apply  only  when  the  organs 
to  be  affected  are  not  only  contiguous,  but  also  continuous  with  those 
directly  affected,  and  offer  no  explanation  of  the  effects  of  irritation  of 
the  skin  upon  the  stomach  or  lungs. 

Much  light  has  been  thrown  on  the  subject  by  the  observations  of 
Mackenzie  and  Head,  who  found  that  visceral  disease  is  often  accom- 
panied by  tenderness  of  the  skin  and  underlying  muscles,  and  that 
the  pain  arising  in  these  cases  is  referred  to  this  area  of  skin  and  not 
to  the  organ  involved.       Thus  in  painful  diseases  of  the  stomach, 


76  SUBSTANCES  ACTING  LOCALLY 

teiulcrness  is  often  found  in  the  skin  and  muscles  of  the  epigastrium, 
wliile  in  a'so])liageal  stricture,  pain  may  be  referred  to  a  ])oint  near 
tlie  angle  of  the  scapula  and  to  another  in  the  neighhorliood  of  the 
apex  beat.  Similarly  in  heart  disease,  pain  is  often  felt  in  the  left 
chest-wall  and  shoulder  extending  down  the  left  arm.  These  points 
are,  of  course,  only  connected  with  the  diseased  organ  by  means  of 
ner\e-fibres,  and  it  thus  appears  that  impulses  from  such  an  organ 
arouse  a  condition  of  heightened  sensibility  in  the  region  of  the  cord 
on  which  they  impinge;  this  afTects  all  the  synapses  in  the  neighbor- 
hood (Fig.  1),  so  that  impulses  from  very  different  structures  may 
be  altered  by  the  affection  of  one.  The  sensation  of  pain  aroused  by 
this  exaggerated  sensibility  is  of  course  referred  to  the  periphery,  not 
to  the  focus  in  the  cord,  and  this  gives  the  impression  of  tenderness 
in  the  skin  and  muscles.  It  therefore  seems  probable  enough  that  an 
affection  of  these  superficial  areas  may  affect  the  corresponding  inter- 
nal organ  more  than  the  rest  of  the  body,  and  this  is  exactly  what  is 
required  to  explain  the  benefits  derived  from  the  use  of  counter- 
irritants.  It  is  especially  noticeable  that  several  of  the  points  affected 
by  internal  disease  are  precisely  those  points  at  which  experience  has 
shown  irritation  to  be  most  beneficial  (Fig.  2).  Thus  the  application 
of  a  blister  over  the  epigastrium  has  long  been  recognized  as  a  means 
of  relieving  gastric  disorders.  Similarly  the  old  treatment  of  iritis  by 
means  of  a  blister  on  the  temple  may  be  justified  by  the  fact  that 
Head  found  areas  of  tenderness  on  the  temple  accompanying  this 
disease. 

The  exact  nature  of  the  effects  of  counter-irritation  on  the  internal 
organs  has  not  been  ascertained,  but  it  would  seem  most  probable  that 
an  alteration  in  the  calibre  of  the  A'essels  is  induced.  These  alterations 
may  be  accompanied  by  changes  in  the  activity  of  the  organs;  for 
example,  there  seems  good  reason  to  believe  that  in  many  cases  irritants 
applied  to  the  abdomen  produce  evacuation  of  the  bowels.  The  most 
obvious  effect  of  counter-irritation  very  often  is  the  relief  of  pain,  and 
this  seems  explicable  in  the  light  of  the  observations  of  jMackenzie 
and  Head.  For  if  the  pain  in  visceral  disease  is  due  to  the  disorder 
of  the  synapses  in  the  spinal  cord  at  the  level  at  which  the  fibres  from 
the  viscus  and  from  the  superficial  tissues  meet,  it  is  possible  that 
new  impulses  reaching  this  area  from  the  skin  may  alter  its  condition 
or  may  occupy  a  common  path  to  the  brain  to  the  exclusion  of  impulses 
arising  from  the  seat  of  disease. 

Besides  these  physiological  effects  of  counter-irritation,  it  must  not 
be  forgotten  that  a  great  impression  is  produced  on  the  patients,  and 
that  some  of  the  benefit  may  be  due  to  hypnotic  suggestion. 

Therapeutic  Uses.  —  Local  irritants  are  applied  occasionally  to  pro- 
duce an  alteration  in  the  nutrition  and  blood  supply  of  the  skin  itself 
and  of  the  subcutaneous  tissues.  Thus  in  some  chronic  infianunatory 
conditions,  with  ellusions  into,  or  indurations  of  the  subcutaneous 
tissues,  the  imj)rovement  of  the  circulation  produced  by  slight  irritation 


SKIN  IRRITANTS  AND  COUNTER-IRRITATION 


i  t 


may  be  of  benefit.  An  example  of  this  is  the  treatment  of  ulcers  of 
old  standing  with  irritants.  Another  case  in  which  a  slight  inflam- 
matory attack  causes  very  obvious  improvement,  is  in  corneal  opacity, 
which  may  be  removed  entirely  in  some  cases  by  the  acute  inflam- 
matory reaction  produced  by  such  irritants  as  abrin.  Probably  a 
similar  efi^ect  is  produced  on  subcutaneous  eflFusions,  as  in  bruises. 
Some  interesting  experiments  on  this  subject  have  recently  been  per- 
formed by  Wechsberg,  who  induced  suppuration  in  both  hind  legs  of 


Fig.  2 


The  right  side  is  divided  into  segments  which  correspond  to  some  of  the  skin  areas 
in  which  Head  found  tenderness  in  internal  diseases.  1.  Area  of  tenderness  in  disease 
of  the  lungs.  2.  In  diseases  of  the  stomach.  3.  In  ovarian  disease.  4.  In  disease  of  the 
Fallopian  tubes  and  other  appendages.  On  the  left  side  are  represented  the  points  of 
appHcation  of  counter-irritants  in  disease  of  the  lungs  {A),  of  the  stomach  (5),  of  the 
ovary  ((7),  and  the  uterine  appendages  (D). 


rabbits  by  the  injection  of  irritants  and  then  treated  the  one  leg  by  the 
application  of  various  irritants  to  the  skin,  while  the  other  was  left 
untreated  as  a  control.  He  invariably  found  the  abscess  of  the  leg 
subjected  to  treatment  less  extensive  and  showing  a  greater  tendency 
to  heal  than  the  other,  and  accounts  for  this  by  the  oedema  induced  by 
the    skin     irritant    diluting  the   original    irritant  and   promoting   its 


78  SUBSTANCES  ACTING  LOCALLY 

absorption.  The  increased  blood  supply  leads  to  a  larger  supply  of 
leucocytes  and  protective  substances  around  the  inflammation  than 
would  otherwise  be  present.  He  found  that  the  absorption  of  pigments 
from  the  rabbit's  ear  was  much  accelerated  by  the  application  of 
irritants  to  the  skin  over  the  part,  and  cites  this  as  evidence  that  toxins 
are  removed  more  rapidly  under  similar  treatment.  For  these  purposes 
only  the  milder  irritants  are  required;  in  fact,  vesication  may  do  more 
harm  than  good.  INIild  irritation  alters  the  sensitiveness  of  the  sen- 
sory organs  of  the  skin,  and  heat  is  often  applied  to  alleviate  pain  and 
discomfort  in  the  skin  itself.  In  other  instances  pain  is  increased  by 
heat,  and,  in  fact,  it  is  sometimes  applied  in  the  treatment  of  local 
anaesthesia,  with  the  object  of  rendering  the  surface  more  sensitive. 
In  many  forms  of  skin  disease,  mild  irritants  are  found  to  be  of 
benefit;  this  is  sometimes  attributed  to  their  antiseptic  action,  but  the 
slight  irritation  is  undoubtedly  of  some  importance. 

Counter-irritants  are  used  in  a  large  number  of  diseases,  often 
without  any  definite  idea  of  what  precise  effects  they  will  elicit,  but 
merel}^  because  they  have  been  found  to  give  relief  in  similar  conditions. 
As  a  general  rule  they  are  placed  over  the  affected  organ,  and  this 
corresponds  fairh^  in  most  cases  of  disease  of  the  trunk  with  Head's 
area  of  skin  tenderness.  In  the  head,  however,  the  segmental  arrange- 
ment has  been  rendered  ver}'  irregular  by  the  compression  in  develop- 
ment, and  counter-irritants  are  often  found  to  be  most  effective  when 
placed  at  some  distance  from  the  seat  of  pain,  e.  g.,  behind  the  ear 
in  some  forms  of  facial  neuralgia.  They  are  used  in  acute  inflammation 
of  the  lungs  and  pleura,  in  gastric  disorders  accompanied  by  much 
pain,  in  colic  and  in  neuralgia  and  neuritis.  Their  action  is  very  uncer- 
tain, but  their  application  is  often  followed  by  great  relief,  more  espe- 
cially of  pain.  They  are  also  used  occasionally  in  shock  or  collapse, 
not  for  their  eft'ect  on  any  individual  organ,  but  to  elicit  the  reflex 
alterations  in  the  circulation  which  have  already  been  described.  A 
blister  is  often  recommended  in  internal  htemorrhage,  and  may  \ery 
possibly  lessen  the  bleeding  by  altering  the  distribution  of  the  blood 
in  the  organs,  although  it  is  difficult  to  estimate  how  far  the  improve- 
ment is  due  to  the  remedy  and  how  far  it  is  spontaneous.  In  order 
to  ])roduce  any  marked  effect  on  internal  organs,  the  more  powerful 
irritants  must  be  used,  such  as  mustard  or  cantharides.  It  is  not 
necessary,  however,  to  produce  actual  vesication  in  the  great  majority 
of  cases.  Formerly  blisters  were  o])ened  and  fresh  irritants  ai)plied 
on  the  raw  surface  in  order  to  prolong  the  etlects,  but  this  treatment 
was  extremely  painful,  besides  being  liable  to  set  up  sujipuration  and 
ulceration,  and  it  is  very  questionable  whether  any  equi\alent  l)enefit 
followed. 

(\)Uiit(T-irritati(»ii  innst  be  a])i)li('(l  only  with  the  greatest  caution  in 
weak,  badly  nourislicd,  or  xcry  old  persons,  as  it  may  cause  sloughing. 
In  diabetes,  the  tendency  to  gangrene  contra-indicates  blistering,  and 
in  \-er\'  Noung  children  onl\   mild  irritants  are  used. 


SKIN  IRRITANTS  AND  COUNTER-IRRITATION  79 


Bibliography. 

Naumann.     Vierteljahrsch.  f.  prakt.  Heilkunde,  Ixxvii,  p.  1  and  xciii,  p.  133. 

Ziilzer.    Deutsche  Klinik.,  1865,  p.  127. 
^ohrig  and,  Zuntz.  Pfliiger's  Archiv,  iv,  p.  57. 
'Paalzow.     Ibid.,  iv,  p.  492. 

Mantegazza.     Schmidt's  Jahrb.,  cxxxiii,  p.  153. 
*-Jacobson.    Virchow's  Archiv,  Ixvii,  p.  166. 

Head.    Brain,  xvi,  p.  1;    xvii.  p.  339. 

Mackenzie.     Symptoms  and  their  interpretation,   1909,  p.  80. 

Winternitz.    Arch.  f.  exp.  Path.  u.  Pharm.,  xxxv,  p.  77;    xxxvi,  p.  212. 

Wessley.     Centralbl.  f.  Chirur.,  xxx.  No.  36. 

Buchner,  Fuchs,  Megele.    Arch.  f.  Hygiene,  xl,  p.  347. 

Wcchsberg.    Ztschr.  f.  khn.  Med.,  xxxvii,  p.  360. 

Erlanger.     Zeitschr.  f.  exp.  Path.  u.  Ther.,  ix,  p.  22. 

An  enormous  number  of  drugs  produce  irritation  of  the  skin,  and  it 
would  be  idle  to  attempt  to  enumerate  them  here.  In  many  instances, 
however,  the  irritant  action  is  insignificant  in  comparison  with  the 
other  effects  produced,  and  these  will,  therefore,  be  discussed  else- 
where; among  these  are  found  some  of  the  alkaloids,  the  acids  and 
alkalies,  and  many  other  inorganic  preparations.  Irritation  of  the 
skin  may  also  be  produced  by  heat  and  cold,  and  in  fact  burning  in 
various  forms  was  formerly  used  as  a  means  of  counter-irritation. 
Heat  is  still  employed  to  cause  irritation  of  the  skin  and  subcutaneous 
tissues,  and  to  promote  their  circulation.  Thus,  poultices,  and  hot 
water  compresses  are  beneficial  in  many  local  inflammations,  though 
the  same  effects  may  generally  be  obtained  by  the  use  of  the  milder 
irritants.  A  variety  of  apparatus  has  been  devised  for  the  application 
of  air  heated  to  250°  F.,  or  even  higher  to  rheumatic  joints,  but  it 
may  be  questioned  whether  the  results  are  more  favorable  than  those 
obtained  by  poultices  and  other  methods.  Another  method  by  which 
hypersemia  of  a  whole  limb  may  be  attained  has  been  introduced 
by  Bier,  who  advises  the  application  above  the  seat  of  disease  of  an 
elastic  bandage  which  is  tight  enough  to  retard  slightly  the  venous 
flow,  but  leaves  the  circulation  of  the  limb  otherwise  intact;  satis- 
factory results  have  been  recorded  from  this  treatment  in  many  con- 
ditions, and  these  are  generally  ascribed  to  the  accumulation  of  leuco- 
cytes and  alexines  in  the  tissues.  Somewhat  similar  results  may  be 
obtained  in  the  trunk  by  dry  cupping,  in  which  the  blood  is  drawn  to 
the  diseased  superficial  tissue  by  applying  a  glass  tightly  to  the  skin 
and  exhausting  the  air  in  its  interior.  Another  method  by  which 
chronic  inflammatory  conditions  have  been  treated  with  the  view  of 
inducing  an  acute  reaction  is  the  application  of  solid  carbonic  dioxide; 
this  has  been  employed  chiefly  in  open  wounds  and  in  disease  of  mucous 
membranes. 

Apart  from  those  drugs  in  which  the  irritation  of  the  skin  is  merely 
an  incident  in  a  wider  general  action,  there  are  a  number  of  prepara- 
tions which  are  used  almost  exclusively  for  this  puropse.  They  may 
be  divided  into  three  classes:  the  volatile  irritants,  such  as  turpentine 


80  SUBSTANCES  ACTING  LOCALLY 

oil;  the  mustard  series,  some  of  which  are  also  volatile;  and  those 
which  are  either  non-volatile  or  only  boil  at  high  temperatures,  such 
as  cantharidin. 

1.  The  Turpentine  OU  Group. 

Under  the  volatile  irritants  may  be  included  a  large  number  of  the 
ethereal  oils  and  many  members  of  the  methane  and  of  the  aromatic 
series;  but  among  the  ethereal  oils  those  which  possess  a  low  boiling 
point,  that  is,  those  which  contain  a  large  proportion  of  terpene,  with 
comparatively  little  oxygen,  are  found  to  possess  a  more  penetrating 
action  than  the  others.  At  the  same  time,  the  taste  and  odor  of  these 
oils  is  often  less  pleasant  than  that  of  the  others,  so  that  they  are  less 
used  as  flavors  and  carminatives.  The  oils  derived  from  the  Conif- 
erse  have,  for  this  reason,  been  more  largely  used  than  the  others  for 
their  effect  on  the  skin,  although  several  other  volatile  preparations 
are  recognized  by  the  pharmacopoeia  for  this  purpose.  The  action  of 
these  oils  is  similar  in  other  respects  to  that  of  the  general  group 
(see  p.  57),  so  that  it  need  not  be  discussed  here. 

Preparations. 

Terebinthina,  turpentine  (U.  S.  P.),  a  concrete  oleoresin  obtained  from 
Pinus  palustris  and  other  species  of  Pinus. 

Oleum  Terebinthince  (U.  S.  P.),  oil  of  turpentine,  a  volatile  oil  distilled 
from  turpentine. 

Oleum  Terebinthin.e  Rectificatum  (U.  S.  P.,  B.  P.),  is  formed  from 
ordinary  oil  of  turpentine  by  redistillation  and  consists  of  a  mixture  of  ter- 
penes  (CioHie).  Dose,  1  c.c.  (15  mins.);  as  an  anthelmintic,  8-15  c.c.  (2-4 
fl.  drs.). 

Emulsum  Olei  Terebinthince  (U.  S.  P.),  4  c.c.  (1  fl.  dr.). 

Linimentum  Terebinthinm  (U.  S.  P.,  B.  P.). 

Linimentum  Terebinthince  Aceticum  (B.  P.),  is  formed  by  mixing  turpen- 
tine, glacial  acetic  acid,  and  camphor  liniment. 

Terebenum  (U.  S.  P.,  B.  P.),  a  liquid  formed  from  oil  of  turpentine  by  the 
action  of  sulphuric  acid.  It  consists  of  a  number  of  tcrpenes,  one  of  which 
is  the  pure  suljstance  known  as  terebene.  Its  odor  is  more  pleasant  than  that 
of  turpentine  oil,  which  it  closely  resembles  otherwise.     Dose  0.5  c.c.  (8  mins.). 

Terpini  Hydras  (U.  S.  P.),  terpin  hydrate,  is  a  crystalline  substance  (doHic 
(Oil),  +  IIjO)  derived  from  oil  of  turpentine  by  the  action  of  nitric  acid  in 
the  i)resence  of  alcohol  and  water.  It  possesses  almost  no  otlor,  is  insoluble  in 
water,  and  molts  at  about  116°  C.     Dose  0.125  G.  (2  grs.). 

Oleum  Juniperi  (U.  S.  P.,  B.  P.),  oil  of  Juniper,  is  derived  from  the  juni- 
per h(;rri('.s  and  consists  mainly  of  terpenes.    Dose,  0.2  c.c.  (3  mins.). 

Si>iritm  Juniperi  (U.  S.  P.,  B.  P.),  2  c.c.  (30  mins.);  B.  P.  5-20  mins. 

Spiritus  Juniperi  Compositus  (U.  S.  P.),  8  c.c.  (2  fl.  drs.). 

In  addition  to  those  jiroparations  the  following  may  be  mentioned  here  as 
possessing  similar  action  and  uses. 

IjiniinvnUtm  Chlornformi  (U.  S.  P.,  B.  P.). 

Llninicnliini  ('(iniphortv  (U.  S.  P.,  U.  P.). 

Lininicntiini  ('iniiplior(v  Annnonidtiini  (H.  P.). 

Linlmcnlinii  Saixmis  {V.  S.  P.,  H.  P.),  very  slightly  iriilant. 

Arnica  and  its  preparations  onjoy  a  jjopular  rojjutation  as  skin  applications 
but  do  not  appi-ar  to  liavo  any  action  which  entitles  them  to  consideration. 


SKIN  IRRirANTS  AND  COUNTER-IRRITATION  81 

Therapeutic  Uses. — Turpentine  oil  is  used  externally  as  a  rubefacient, 
and  differs  from  mustard  and  cantharidin  in  its  greater  penetrating 
power.  It  is  not  so  irritant,  however;  it  blisters  only  after  long  applica- 
tion, and  the  vesication  produced  is  very  painful  and  heals  slowly, 
from  the  vapor  penetrating  into  the  deeper  tissues.  It  is,  therefore, 
employed  to  produce  rubefaction  only,  and  ought  to  be  removed 
when  this  is  attained.  For  this  purpose  any  of  the  liniments  of  the 
group  may  be  employed,  or  a  more  intense  action  may  be  got  from  the 
"turpentine  stupe,"  which  is  made  by  dipping  flannel  in  hot  water, 
wringing  it  dry,  and  then  dropping  warm  turpentine  oil  on  it.^  Tur- 
pentine preparations  are  used  especially  in  rheumatic  affections  of  the 
joints  or  muscles,  and  in  sciatica.  The  oleoresin  may  be  formed  into 
ointment,  or  plaster,  and  used  as  a  feeble  stimulant  in  skin  diseases. 
Turpentine  oil  is  a  fairly  strong  antiseptic,  and  is  less  irritant  than 
many  of  the  more  powerful  ones.  It  is  often  inhaled  in  lung  diseases 
such  as  tuberculosis  or  gangrene,  and  has  the  effect  of  lessening  the 
odor  in  the  latter;  the  oil  may  be  simply  allowed  to  evaporate,  but  is 
much  more  efficient  when  sprayed  into  the  air.  ]\Iany  of  the  resorts 
for  phthisical  patients  are  stated  to  be  rendered  especially  suitable 
for  this  disease  by  the  neighborhood  of  coniferous  forests,  which  are 
supposed  to  dissipate  the  oils  into  the  atmosphere;  but  this  is  probably 
only  an  insignificant  factor  in  the  treatment.  Turpentine  oil  is  occasion- 
ally added  to  baths  in  order  to  cause  a  slight  general  irritation  of  the 
skin,  which  may  be  of  benefit  in  some  skin  diseases  and  also  in  general 
debility  under  certain  conditions;  and  pine-needle  baths  have  some 
reputation  in  Germany  for  the  same  reason,  the  water  being  supposed 
to  extract  the  oil. 

Internally,  turpentine  oil  is  occasionally  employed  as  a  vermifuge, 
but  is  inferior  to  other  preparations  used  for  this  purpose.  A  few 
drops  are  often  added  to  purgative  enemata  to  increase  their  efficiency. 
It  has  been  given  by  the  mouth  in  order  to  lessen  flatulence  and  to 
disinfect  the  intestine  in  various  diseases,  among  others,  typhoid 
fever,  although  its  value  here  is  disputed.  Preparations  of  turpentine 
oil  and  juniper  are  reliable  and  fairly  powerful  diuretics,  but  must 
not  be  prescribed  in  irritation  of  the  kidney.  The  turpentine  prepara- 
tions have  a  certain  reputation  as  expectorants,  and  terebene  has  been 
especially  advised  for  this  purpose;  they  are  also  given  internally 
as  pulmonary  disinfectants  and  in  neuralgia  and  internal  hemorrhage, 
and  are  probably  entirely  valueless  for  these  purposes.  Old  oil  of 
turpentine  was  formerly  advocated  in  phosphorus  poisoning,  but  this 
treatment  has  proved  to  be  erroneous. 

Along  with  these  may  be  mentioned  a  series  of  resins  which  have  some 
slight  irritating  effect  on  the  skin,  and  have  been  used  in  the  treatment  of 
skin  diseases. 

'  Alcohol  has  recently  been  applied  in  a  similar  way  in  phlegmon  and   other  forms 
of  inflammation.     Gauze  is  soaked  in  alcohol  (60-96  per  cent.),  wrung  out,  wound  round 
the  affected  part  and  covered  with  cotton  and  oil-clotli. 
6 


82  SUBSTANCES  ACTING  LOCALLY 

Resina  (U.  8.  P.,  B.  P.),  resin,  colophony,  is  the  residue  left  after  distilling 
off  the  volatile  oil  from  turpentine. 

Ceralum  Iicsina'{l].H.'P.). 

Ccratutn  Resina'  Compositum  (U.  S.  P.). 

Einplastnim.  Reduce  (B.  P.),  adhesive  plaster. 

I'nguintKm  Resina;  (B.  P.). 

Guaiacum  (U.  S.  P.),  Guaiaci  Resina  (B.  P.),  the  resin  obtained  from  Guaia- 
cum  officinale,  contains  several  resinous  acids,  some  volatile  oils  and  gums. 
It  is  colored  deep  blue  bv  oxidizing  agents. 

Tinctura  Cniaiaci  (U.  S."'P.),  4  c.c.  (1  fi.  dr.). 

Tinctura  Guaiaci  Ammoniata  (U.  S.  P.,  B.  P.),  2  c.c.  (30  mins.).  B.  P. 
^,-1  fl.  dr. 

Myrrha  (U.  S.  P.,  B.  P.),  a  gumresin  obtained  from  Commiphora  Ah-rrha 
(U.  S.  P.),  from  Balsamodendron  Myrrha  (B.  P.),  containing  a  small  quantity 
of  volatile  oil 

Tinctura  Myrrliw  (U.  S.  P.),  1  c.c.  (15  mins.);   B.  P.,  30-60  mins. 

Many  other  resins  have  been  used  in  therapeutics,  but  have  been  aban- 
doned, a  fate  bj-  which  these  survivors  seem  to  be  threatened.  They  are  oc- 
casionally used  externally  as  mild  irritant  applications  in  skin  affections.  Gal- 
banum,  Ammoniacum,  Guaiacum,  and  Myrrh,  have  been  used  internally  for 
many  different  purposes,  as  expectorants,  diaphoretics,  diuretics,  aperients, 
and  have  enjoyed  a  reputation  in  the  treatment  of  amenorrhcea.  They  may  be 
used  to  suspend  insoluble  bodies,  as  the  gum  contained  causes  them  to  form 
emulsions  when  water  is  added. 

2.  Mustard. 

Mustard  occurs  in  two  forms  in  the  pharmacopoeias,  Black  ]\Iustard, 
Sinapis  nigra,  and  White  Mustard,  Sinapis  alba.  Black  Mustard 
contains  a  glucoside,  Potassium  Myronate  or  Si7iigrin,  and  a  ferment, 
Myrosin,  which  decomposes  it  in  the  presence  of  water  into  dextrose, 
potassium  bisulphate  and  allyl-isosulphocyanate  or  volatile  oil  of 
mustard. 

Sinigrin.  Volatile  oil. 

C10H18KNS2O10  =  CSNC3H5  +  CeHnOe  +  KHSO4 

Volatile  oil  of  mustard  is  formed  in  various  other  Cruciferse  when  thc>-  are 
mixed  with  water.  Thus  horseradish  root  (Armoracia,  B.  P.)  contains  it.  while 
the  allied  species  Cochlearia  officinalis  apparently  contains  the  corresponding 
isobutyl  compound. 

Wliite  mustard  contains  another  glucoside,  Sinnlbiii,  which  is  also 
decomposed  by  the  Myrosin  in  the  presence  of  water.  The  products 
are  entirely  different,  however,  dextrose,  sulphate  of  sinapine  (an 
alkaloid),  and  an  oil  of  mustard  containing  an  aromatic  nucleus  being 
formed. 

Sinalbin.  Oil  of  mustard.  Sinapine  sulphate. 

r3oH«NjS.Oi6  =  C6Hi(OH)CH2NCS  +C16HMNO5H2SO1  +  CeHi-O. 

The  oil  of  white  mustard  differs  from  that  of  the  black  in  being 
less  irritant,  and  in  being  destroyed  by  heat. 

Action. — Either  of  these  oils  is  intensely  irritant  when  applied  to 
the  skin,  and  if  left  long  enough  j^roduces  i)]isteriiig,  which  is  more 
painful    than    that    caused    by    canthariiles,  and    is    said  to  heal  less 


SKIN  IRRITANTS  AND  COUNTER-IRRITATION  S3 

readily.  This  is  probably  due  to  the  oils  penetrating  more  deeply 
into  the  tissues,  and  thus  setting  up  more  extensive  inflammation. 
Mustard  is  accordingly  used  only  to  induce  rubefaction,  and  ought  to 
be  removed  before  actual  vesication  occurs.  When  the  crude  drug  is 
moistened  and  applied  to  the  skin,  the  oil  is  formed  only  slowly,  so 
that  the  longer  it  remains  applied,  the  more  intense  is  the  action. 
The  glucosides  iij  themselves  have  little  or  no  action,  and  the  products 
of  their  decomposition  are  harmless,  with  the  exception  of  the  oils. 

Preparations. 

Sinapis  Alba  (U.  S.  P.),  the  dried  ripe  seeds  of  Brassica  alba. 

Sinapis  Nigra  (U.  S.  P.),  the  dried  ripe  seeds  of  Brassica  nigra. 

Charta  Sinapis  (U.  S.  P.),  black  mustard  powder  rendered  adhesive  l)y 
India-rubber,  applied  to  sheets  of  paper  and  dried. 

Oleum  Sinapis  Volntile  (U.  S.  P.,  B.  P.),  derived  from  black  mustard. 

Lmimentum  Sinapis  (B.  P.),  formed  from  volatile  oil  of  mustard,  camphor, 
and  castor  oil. 

Uses. — Mustard  is  largely  used  as  a  condiment  and  to  promote 
appetite,  but  is  never  prescribed  for  this  purpose.  In  large  quantities 
it  causes  violent  irritation  of  the  stomach  and  bowel,  with  vomiting, 
purging,  acute  pain  and  tenderness  in  the  abdomen,  and  collapse. 
Mustard  and  warm  water  is  a  convenient  emetic  in  emergencies,  as  in 
cases  of  poisoning. 

The  plaster  or  leaf  (charta)  is  the  form  in  which  it  is  generally  used 
in  therapeutics.  It  contains  the  glucoside,  which  is  slowly  decom- 
posed by  the  ferment  when  the  plaster  is  dipped  in  warm  water  for  a 
few  minutes  before  application.  Another  popular  application  is  the 
mustard  poultice,  in  which  powdered  mustard  is  sprinkled  on  an  ordi- 
nary poultice.  Mustard  is  also  added  to  baths  occasionally  when 
slight  irritation  and  consequent  congestion  is  desired  over  a  large 
surface.  For  this  purpose  2-4  teaspoonfuls  of  the  dry  powder  are 
added  for  each  gallon  of  water.  In  preparations  of  mustard  it  is 
important  to  avoid  a  temperature  of  over  60°  C.  (140°  F.),  as  the 
ferment  is  destroyed  above  this.  The  plaster  is  left  on  the  skin  only 
for  15  to  30  minutes,  when  it  is  used  as  a  rubefacient. 

3.  Cantharidin  Series. 

Another  series  of  local  irritants  comprises  non-volatile  substances, 
of  which  cantharidin  (C10H12O4)  is  the  best  known.  It  is  an  anhydride 
and  when  acted  on  by  bases  forms  cantharidates,  which  resemble  it 
in  action.  It  is  found  in  Spanish  fly  (Cantharis  vesicatoria,  or  Lytta 
yesicatoria)  and  in  several  allied  species  of  Coleoptera  (beetles). 

Action. — Applied  to  the  skin,  cantharidin  produces  redness,  smart- 
ng  and  pain,  followed  very  soon  by  small  vesicles,  which  later  coalesce 
nto  one  large  blister.  This  is  much  less  painful  than  the  vesication 
)roduced  by  mustard,  because  less  of  the  irritant  penetrates  into  the 
leeper  tissues  than  in  the  case  of  the  volatile  mustard  oil.       If  the 


84  SUBSTANCES  ACTING  LOCALLY 

blister  be  broken,  however,  and  the  nnprotected  dermis  \)v  allowed  to 
come  in  contact  with  the  irritant,  violent  inflammation  with  much 
l^ain,  suppuration  and  even  slou}3;hing  may  follow. 

When  larife  quantities  of  cantharidin  are  given  internally,  the  same 
irritant  action  takes  place  along  the  alimentary  tract.  If  taken  in 
solution,  blisters  arise  in  the  mouth  and  throat,  and  the  pain  and 
swelling  in  the  oesophagus  may  be  so  acute  as  to  prevent  swallowing. 
The  irritation  of  the  stomach  produces  vomiting,  followed  by  purging 
with  excruciating  pain  in  the  abdomen,  and  all  the  symptoms  of  shock 
and  collapse. 

Cantharidin  is  absorbed  from  the  alimentary  canal,  and  also  to  a 
less  extent  from  the  skin,  but  has  no  important  action  on  the  internal 
organs,  with  the  exception  of  those  by  which  it  is  eliminated.  Vomiting 
occurs  on  subcutaneous  injection  from  some  of  the  poison  being  excreted 
into  the  alimentary  tract.  Comparatively  small  quantities  irritate 
the  bladder,  and  cause  a  constant  desire  to  micturate,  with  pain  in 
doing  so.  In  somewhat  larger  amount  it  sets  up  an  acute  nephritis 
with  albuminuria,  pain  in  the  kidney  region,  and  sometimes  blood  in 
the  urine.  The  inflammation  of  the  bladder  and  urethra  produces 
intense  pain  and  often  priapism;  in  w^omen  abortion  is  said  to  occur 
occasionally,  and  in  both  sexes  the  irritation  may  lead  to  increased 
sexual  desire. 

The  irritation  of  the  kidneys  by  small  doses  increases  their  secretion, 
and  cantharides  was  therefore  considered  a  diuretic  formerly.  The 
tendency  to  produce  nephritis  renders  it  a  dangerous  internal  remedj'', 
however,  and  its  diuretic  power  is  quite  insignificant  in  comparison 
with  that  of  caft'eine. 

Animals  vary  very  considerably  in  the  degree  in  whicli  they  react  to  can- 
tharidin, the  most  noted  example  being  the  hcdgeliog,  which  is  capable  of 
surviving  a  dose  of  the  poison  sufticient  to  poison  an  adult  man.  Prowls  and 
rabbits  also  possess  a  high  degree  of  congenital  tolerance  for  this  poison,  although 
none  of  these  is  absolutely  insusceptible  to  it. 

Preparations. 

U.  S.  P. — Cantharis,  Spanish  Fly,  the  dried  beetle,  Cantliaris  vesicatoria. 
Ceratum  Caxthauidis  (U.  S.  P.). 
Collodiuni  ('(itdharidatum  (U.  S.  P.). 
Tindurd  ('(nitlidridl.s  (U.  S.  P.),  0.3  c.c.  (5  mins.) 

]i.  P. — Cantharidinum,  CioHi.Oi,  ol)tained  from  ^  arious  species  of  Cantharis 
or  of  AIyla])ris. 

l^Mi'LASTiii'M  Canthakidini,  containing  0.2  per  cent. 
l^^a'LASTRUM  Calefaciens,  wanning  plaster,  0.02  per  cent. 
U miucidum  Caidhdridini,  0.033  ])er  cent. 
Liquor  EpisiKisticus,  hUstering  liciuid.  0.04  ])er  cent. 
Tindura  Cantharidini,  0.01  per  cent.  2  5  mins. 

Therapeutic  Uses.  'I'll is  drug  is  at  present  us(h1  almost  exclusively 
as  a  skin  irritant,  and  more  particularlx'  as  a  vesicant.  In  the  Tnited 
States  the  cerate  is  generally  used  for  this  purpose,  and  is  ai)plied  to 


SKIN  IRRITANTS  AND  COUNTER-IRRITATION  85 

the  skin  by  means  of  adliesive  plaster;  the  corresponding  preparation 
of  the  B.  P.  is  the  cantharidin  phister.  It  is  to  be  noted  that  in  order 
to  produce  actual  blistering,  the  plaster  has  to  remain  in  contact  with 
the  skin  some  8-10  hours,  but  an  equal  effect  may  be  achieved  by 
replacing  the  plaster  by  a  hot  poultice  after  4-G  hours,  when  the  skin 
irritation  has  reached  the  stage  of  redness.  Cantharides  is  also  used 
to  cause  rubefaction  and  commencing  vesication  (flying  blister);  this 
may  be  done  by  the  use  of  these  preparations,  or  by  means  of  the 
warming  plaster,  B.  P.  Blistering  collodion  or  blistering  liquid,  is  used 
rarely  in  unmanageable  cases  in  which  there  is  a  risk  of  the  plaster 
being  removed  by  the  patient.  The  ointment  is  said  to  induce  blister- 
ing sooner  than  the  plaster. 

Cantharidin  is  liable  to  be  absorbed  from  the  skin,  and  its  application 
is  therefore  avoided  where  there  is  any  tendency  to  renal  inflammation. 

Cantharides  has  been  used  not  infrequently  as  an  aphrodisiac,  and 
several  cases  of  poisoning  have  occurred  from  its  administration  for 
this  purpose.  In  cattle  it  is  largely  employed  to  this  end  in  some 
countries,  and  in  man  it  has  undoubtedly  similar  effects  in  some  cases 
through  the  irritation  of  the  bladder  and  urethra,  but  its  use  for  this 
purpose  is  always  liable  to  produce  nephritis.  As  an  emmenagogue, 
cantharides  has  a  certain  popular  reputation,  w-hich,  however,  has  been 
shown  to  be  unmerited,  any  influence  which  it  may  possess  on  the 
menstrual  flow  being  quite  insignificant,  and  probably  due  only  to  the 
irritation  of  the  bladder  and  urethra. 

Cantharides  has  been  advised  internally  in  some  forms  of  renal  and  vesical 
disease,  but  it  is  an  exceedingly  dangerous  remedy  in  these  conditions.  It 
is  sometimes  a  constituent  of  hair  washes,  its  irritant  action  on  the  skin  being 
credited  ^-ith  causing  a  more  rapid  growth  of  the  hair. 

In  cases  of  Poisoning  with  cantharides,  the  stomach  ought  to  be 
emptied  as  rapidly  as  possible  by  the  stomach  tube,  provided  the 
oesophagus  allows  of  its  passage.  Demulcents  and  albuminous  sub- 
stances are  of  use  in  slowing  the  absorption,  but  all  oily  or  fatty  bodies 
must  be  avoided,  as  they  tend  to  dissolve  the  cantharidin  and  thus 
promote  its  absorption.  Opium  may  be  given  for  the  pain,  and  if 
collapse  sets  in,  the  ordinary  measures  must  be  taken  to  combat  it. 
Ellinger  states  that  the  action  on  the  kidney  in  rabbits  is  more  severe 
when  the  urine  is  acid  than  when  it  is  alkaline,  and  this  suggests  the 
treatment  of  the  renal  symptoms  with  alkalies. 

Poison  Ivy  and  Poison  Oak. — The  commonest  form  of  poisoning  in 
the  United  States  is  the  skin  eruption  produced  by  the  leaves  of  poison 
ivy  and  poison  oak  (Rhus  toxicodendron  and  venenata),  which  Pfaff 
showed  to  be  due  to  the  presence  of  a  neutral  body,  Toxicodendrol; 
this  has  recently  been  stated  to  be  of  glucosidal  nature.  The  effects 
of  poison  ivy  can  arise  only  from  touching  the  plant,  the  poisonous 
principle  not  being  volatile.  Very  minute  quantities  of  toxicodendrol 
are  suflScient  to  produce  skin  eruptions,  however,  xuVir  "^f?-  causing 


86  SUBSTANCES  ACTING  LOCALLY 

distinct  syniptoins  in  susceptible  persons.  The  popular  belief  that 
skin  affections  can  be  induced  by  approaching  the  plant,  without 
actually  touching  it,  is  probably  accounted  for  by  the  facts  that  the 
eruption  may  be  very  late  in  making  its  ai)pcarance,  and  that  poison 
ivy  is  very  fre(iuently  mistaken  for  harmless  climbing  plants.^  The 
statement  that  the  poison  ivy  does  not  affect  some  individuals  is  also 
probably  erroneous,  though  persons  of  delicate  skin  are  undoubtedly 
more  susceptible.  Immunity  is  not  acquired  for  the  poison  by  repeated 
attacks  of  dermatitis. 

In  the  dermatitis  from  poison  ivy,  Pfaff  recommends  the  skin  to 
be  washed  and  scrubbed  with  soap  and  water,  or  with  alcohol,  or  a 
solution  of  lead  acetate  in  alcohol.  Ointments  and  oily  liniments  are 
to  be  avoided,  as  they  dissolve  the  toxicodendrol  and  tend  to  spread  it 
over  the  skin  and  thus  produce  further  inflammation.  For  the  same 
reason,  the  alcohol  used  to  "wash  the  part  must  be  removed  entirely,  as 
the  poisonous  principle  is  soluble  in  it,  while  insoluble  in  water. ^  Potas- 
sium permanganate  solution  is  said  to  be  an  efficacious  application. 

Eruptions  similar  to  that  from  poison  ivy  arise  from  contact  with 
a  number  of  other  plants  of  which  the  best  known  is  the  Primula  oh- 
conica;  this  plant  secrets  some  unknown  substance  which  is  intensely 
irritant  to  the  skin  of  many  people,  and  has  frequently  given  rise  to 
severe  inflammation  in  gardeners  and  others.  Cash  found  an  alkaloid 
obtained  from  East  India  Satinwood  {ChJoroxylon)  equally  irritant 
when  applied  to  the  skin;  the  dermatitis  from  these  bodies  often  appears 
only  2-3  weeks  after  contact  with  them,  and  even  after  apparently 
complete  recovery  the  skin  remains  especially  sensitive  to  a  reapplication 
of  the  poison. 

A  number  of  the  Ranuiiculaeeie  are  irritant  to  the  skia  like  cautharides,  but 
the  active  constituent  has  not  been  definitely  determined.  Mezereum,  which 
was  formerly  official,  is  similarly  irritant,  apparently  from  the  presence  of  an 
irritant  oil  (Sprinsenfeldt).  Cardol,  found  in  the  fruits  of  Anacardmm  occi- 
dental and  in  Semecarpus  anacardium,  is  a  very  powerful  irritant,  and  has 
been  used  to  a  limited  extent  as  a  vesicant.  Cardol  is  i)robably  a  mixture  of  a 
number  of  substances,  but  it  is  unknown  to  which  of  these  it  owes  its  activity. 
Euphorbin  is  said  by  Buchheim  to  be  the  irritant  i)rincip]e  in  the  Euphorbia  resin 
(Euphorbia  resinicra,  etc.),  and  to  reseml^le  cantharidin  in  its  anhydride  form, 
but  the  salts  and  the  (uipliorhic  acid  which  is  foriniHl  from  them  by  acids  arc 
inactive.  A  very  pois[)iious  member  of  the  Euphorbiacea*  is  the  Alanicheel  tree, 
growing  in  tlu;  West  Indies,  and  it  apparently  Ix'longs  tn  this  series. 

Capsicum  (p.  54)  contains  one  or  more  non-volatile  irritant  substances  and 
is  used  occasionally  as  a  skin  irritant.  Pepper  is  also  used  as  a  rubefacient  in 
domestic  medicine. 

Chaulmoogra  Oil,  obtained  from  Taraktogenos  Kurzii,  is  apparently  similar 
in  character  to  the  members  of  this  grouj),  although  it  is  less  irritant.  It  is 
used  externally  as  an  application  to  bruises,  and  l)oth  externally  antl  inter- 
nally in  le]m)sy,  although  it  is  probably  of  little  avail  in  this  disease.  Croton 
oil  has  also  been  used  as  a  skin  irritant,  but  will  be  treated  of  in  connection 
with  the  i)urgatives  (page  90). 

Many  other  jjlants  possess  irritant,  poisonous  properties,  which  would  ap- 
parently entitle  tlieni  to  a  place  in  this  series,  but  so  little  is  known  of  their 
active  principles  and  of  fiicii'  (-nccls,  llml  they  may  !)(•  oniitled  U)v  {\\c  present. 


PURGATIVES  87 


Bibliography. 

Aufrrcht.     Ccntralbl.  f.  meil.  Wisscnsch.,  1SS2,  pp.  545,  849. 
^EUinger.    Arch.  f.  cxp.  Path.  u.  Pharm.,  Iviii,  p.  424.     Mimchen.  med.  Woch.,  1005. 

Liebrcich.    Therap.  Moiiatsheft,  1891,  p.  169;    1892,  p.  294;    1895,  p.  167. 

Buchheim.     Arch.  d.  Heilkunde,  xiii,  p.  1. 

Rost  u.  Gilg.     Ber.  Deutsch.  Pharm.  Gesell.,  xxii,  p.  296.     (Poison  Ivj^ 

Lewin.     Deutsch.  med.  Woch.,  1901,  p.  184. 

Pfaff.     Journ.  of  Exp.  Med.,  ii,  p.  181.     (Toxicodendrolr)- 

Warren.     Pharm.  Journ.  and  Trans.,  1909,  pp.  531,  562. 
-^Acree  and  Syme.    Journ.  Biol.  Chcm.,  ii,  p.  547. 

Springenfeldt.     Inaug.  Diss.,  Dorpat.,  1890.     (Mezereum.) 

Cash.    Brit.  Med.  Journ.,  October  7,  1911.     (Chloroxyloftr) 

Noel  et  Lambert.     Arch,  de  Pharmacodyn.,  iv,  p.  169.     (Pulsatilla  and  anemonim^ 


Vin.    PURGATIVES. 

Purgatives  are  drugs  which  are  employed  in  medicine  to  evacuate 
the  bowel  of  its  contents.  Many  drugs  produce  evacuation  in  the 
course  of  their  action,  but  have  other  effects  of  importance  and  are  not 
included  in  this  class.  Thus  the  members  of  the  preceding  class  of 
skin  irritants  induce  diarrhoea,  but  this  is  accompanied  by  irritation  of 
the  mouth,  throat  and  stomach,  and  in  many  other  forms  of  poisoning, 
diarrhoea  is  a  prominent  feature,  but  is  accompanied  by  vomiting  or 
some  other  symptom.  The  ideal  purgative  is  devoid  of  any  effects 
whatsoever,  save  in  the  intestine;  it  passes  through  the  stomach  with- 
out materially  deranging  its  function,  and  is  not  absorbed,  or  at  any 
rate  is  absorbed  so  slowly  that  it  has  time  to  unfold  its  action  through- 
out the  intestine.  The  vegetable  purgatives  act  through  their  irritant 
properties,  which  in  some  instances  are  elicited  only  by  the  action  of 
the  secretion  of  the  intestines  and  of  the  neighboring  glands.  Thus 
some  of  the  purgatives  pass  through  the  stomach  in  the  form  of  bland, 
non-irritant  compounds  (castor  oil),  which  are  broken  up  by  the  digestive 
processes  in  the  intestine,  while  others  perhaps  owe  their  activity  in 
the  intestine  to  their  solution  or  supeusion  in  the  juices. 

Many  classifications  of  the  purgatives  have  been  based  on  their 
effects,  and  some  of  the  terms  are  still  retained,  such  as  aperient, 
eccoprotic,  laxative,  purgative,  cholagogue,  hydragogue,  cathartic,  or 
drastic.  But  the  effect  of  the  purgatives  is  determined  largely  by 
the  dose  and  by  the  condition  of  the  intestine,  so  that  a  small  dose  may 
act  as  an  aperient,  laxative  or  eccoprotic,  while  a  larger  quantity  of 
the  same  drug,  or  even  the  same  dose  in  a  more  susceptible  individual, 
may  act  as  a  drastic  or  hydragogue  cathartic.  They  are  therefore 
classified  in  three  groups:  (1)  the  mild  aperients,  castor  oil  group;  (2) 
the  purgatives  of  the  anthracene  series;  (3)  the  jalap  and  colocynth 
group. 

Symptoms. — In  moderate  doses  the  purgatives  simply  hasten  the 
normal  movements  of  the  intestines,  and  the  stool  is  of  the  ordinary 
appearance  and  consistency  (laxative,  aperient,  or  eccoprotic  action). 
In  larger  quantities  they  cause  a  more  profuse  evacuation  than  normally, 
and  the  stools,  which  are  repeated  at  short  intervals,  are  of  a  looser, 


88  SUBSTANCES  ACTING  LOCALLY 

more  lluid  consistency.  Tlicir  action  is  accompanied  In-  considerable 
pain  and  colic,  and  the  hurried  movements  of  the  intestine  are  shown 
by  the  characteristic  gurgling  sounds.  Large  quantities  of  the  more 
powerful  i^urgatives  may  cause  all  the  symptoms  of  acute  enteritis, 
the  stools  at  first  contain  the  ordinary  faecal  substances  accompanied 
by  more  fluid  than  usual,  but  later  consist  largely  of  blood-stained 
mucous  fluid  with  little  or  no  resemblance  to  ordinary  faeces.  This 
violent  purgation,  which  is  not  induced  in  therapeutics,  is  accom- 
l)anied  by  i)ain  and  tenderness  in  the  abdomen,  and  may  induce  shock, 
collapse,  and  eventually  death. 

Action. — The  origin  of  the  fluid  of  the  stools  after  purgatives  has 
been  much  debated.  According  to  many  authors,  they  accelerate  the 
passage  of  the  intestinal  contents  so  much  that  there  is  no  time  for 
the  absorption  of  the  fluid,  and  the  fivces  escape  in  the  fluid  condition 
in  which  they  normally  exist  in  the  small  intestine.  (3ther  investigators 
hold  that  purgatives  cause  fluid  to  pass  into  the  intestine,  either  by 
increasing  the  normal  secretions,  or  by  causing  an  inflammatory 
exudate  from  the  vessels.  These  contradictory  views  are  probably 
due  to  the  methods  adopted,  and  the  quantity  of  the  drug  used.  In 
small  quantities,  such  as  are  used  in  the  vast  majority  of  cases  in  thera- 
peutics, the  irritation  produced  by  the  purgatives  is  apparently  only 
enough  to  accelerate  peristalsis  somewhat,  and  the  fluid  of  the  stools 
is  drawn  partly  from  the  food  and  partly  from  the  ordinary  secretions 
of  the  digestive  organs.  In  these  cases  the  intestine  is  not  actually 
inflamed,  although  some  congestion  may  occur  in  it,  as  in  all  organs  in 
a  state  of  abnormal  activity.  On  the  other  hand,  when  large  quantities 
are  ingested  a  true  inflammation  of  the  inte^stine  occurs,  manifested 
l)y  increased  movement,  congestion,  exudation  of  fluid  into  the  lumen 
of  the  bowel,  and  pain.  In  these  cases  the  intestine  presents  the 
usual  signs  of  inflammation;  it  is  red  and  congested,  and  contains  a 
muco-purulent  fluid  and  often  blood.  The  matter,  therefore,  resolves 
itself  into  a  (juestion  of  dose;  if  it  be  small,  the  fluid  is  not  an  exudate, 
if  it  V)e  large  the  fluid  is  ])artly  an  inflammatory  ])ro(luct.  The  stools 
following  the  atlministration  of  purgatives  difl'er  from  the  normal 
faeces  in  containing  a  larger  proportion  of  water  and  also  of  soluble 
substances.  In  fact,  they  resemble  rather  the  contents  of  the  small 
intestine  than  the  normal  excreta,  and  contain  bodies  which  would 
normally  have  been  absorl)ed  and  utilized,  but  which  have  been  hurried 
through  the  bowel  too  rapidly  to  permit  of  their  being  taken  up  by  the 
epithelium. 

The  colic  produced  by  purgatives  is  not  due  to  the  inflammation  of 
the  intestinal  wall,  but  is  explained  by  the  more  vigorous  contractions 
of  the  walls  of  the  bowel  and  the  diflicult\-  in  forcing  on  hard  ftecal 
masses  in  the  large  intestine.  Tlic  tenderness  produced  by  large 
(piantities  of  the  purgatives,  on  tlic  other  hand,  would  seem  to  indicate 
inflammation. 

In  the  accelerated  peristalsis  ordinarily  induced  by  the  purgatixes, 
the  central  nerxous  svstem  is  not  inxobcd;   the  irritation  of  the  mucous 


PURGAriVKS  89 

membrane  renders  it  more  sensitive  to  the  stimuli  which  it  ordinarily 
receives  from  the  contents,  and  the  nervous  impulses  resulting  from 
these  are  transmitted  to  the  intestinal  nervous  plexus  and  give  rise  to 
the  reHex  inhibition  and  contraction  of  the  nuiscular  coats  by  which 
the  i)eristaltic  movement  is  carried  out. 

The  different  purgatives  seem  to  act  on  different  parts  of  the  bowel 
(Magnus).  Thus  senna,  and  in  all  probability  the  other  anthracene 
purgatives,  appear  to  have  no  effect  on  the  movements  of  the  stomach 
and  small  intestine,  but  act  only  in  the  large  intestine;  the  contents 
reach  the  colon  at  the  normal  rate,  but  as  soon  as  they  have  left  the 
small  bowel,  rapid  movement  begins  and  they  are  evacuated  almost 
immediately.  Castor  oil  on  the  other  hand  accelerates  the  peristalsis 
of  the  small  intestine,  through  which  the  food  passes  very  rapidly,  while 
the  large  gut  is  much  less  irritated.  Colocynth  quickens  the  movement 
of  both  small  and  large  intestine  and  considerable  quantities  of  fluid 
are  effused  into  the  lumen.  All  three  arrest  the  antiperistaltic  move- 
ments in  the  large  intestine. 

Some  of  the  purgatives  cause  evacuation  of  the  bowel  when  they  are 
injected  subcutaneously  or  intravenously  (senna,  aloes,  cascara,  colo- 
cynth, podophyllum),  and  croton  oil  has  long  been  rubbed  on  the  skin 
in  order  to  relieve  constipation,  and  is  found  to  cause  intestinal  inflam- 
mation and  purging  when  injected  intravenously.  It  has  accordingly 
been  suggested  that  these  have  a  specific  action  on  the  bowel  quite 
apart  from  their  irritant  effects;  but  it  is  probable  that  their  intestinal 
effects  are  here  due  to  their  excretion  into  the  bowel,  which  has  been 
shown  to  occur  in  several  instances.  Other  irritants  applied  subcutane- 
ously or  intravenously  often  produce  similar  effects  on  the  alimentary 
canal. 

The  interval  which  elapses  between  the  administration  of  a  purga- 
tive and  its  eft'ects  varies  with  the  dose,  and  also  with  the  individual 
drug.  In  ordinary  therapeutic  doses,  evacuation  of  the  bowels  occurs 
in  most  cases  in  5-10  hours,  but  if  large  quantities  of  the  more  powerful 
purges,  such  as  jalap  or  croton  oil,  be  given,  the  effects  may  be  elicited 
in  two  hours.  Aloes  and  podophyllum  differ  from  the  others  in  the 
length  of  the  interval,  catharsis  rarely  or  never  occurring  earlier  than 
10-12  hours  after  their  administration,  and  often  only  after  20-24 
hours. 

The  movement  of  the  intestine  induced  by  purgatives  is  accom- 
panied by  an  increase  in  the  leucocytes  of  the  blood  similar  to  that 
observed  in  other  forms  of  intestinal  activity,  e.  g.,  during  digestion. 

The  effects  of  the  purgatives  vary  greatly  in  different  animals. 
Thus,  the  rabbit  is  very  refractory  to  most  of  the  series,  and  often  is 
killed  by  intestinal  irritation  without  any  evacuation  being  produced. 
The  frog  is  unaffected  by  quantities  which  would  produce  poisoning 
in  man,  while  the  dog  and  cat  respond  much  more  readily. 

It  was  formerly  supposed  that  purgatives  increased  the  secretion  of 
bile,  and  certain  of  them,  which  were  believed  to  have  a  special  activity 
in  this  direction,  were  known  as  Cholagogues.      It  has  been  shown  of 


90  SUBSTANCES  ACTING  LOCALLY 

recent  years  that  none  of  them  possesses  any  action  on  the  secretion  of 
bile,  altlioiigh  they  may'  increase  its  excretion  by  hurrying  it  tliroiigli 
tlie  intestine  and  preventing  its  reabsorption.  On  the  other  hand, 
the  i)resence  of  ImIc  in  the  intestine  is  a  coiuhtion  necessary  to  the 
activity  of  many  of  the  purgatives.  Thus  Buchheim  and  Stadelmann 
found  that  in  the  absence  of  bile  podophyllum,  jalap,  scammony, 
rhubarb,  and  gamboge  are  either  quite  inactive  or  very  much  less 
powerful  than  usual.  This  is  probably  due  to  some  solvent  action  of 
the  bile,  for  Stadelmann  found  that  when  soaps  were  given  with  some 
of  these  drugs  their  activity  returned,  and  in  other  cases  a  comparatively 
slight  modification  of  their  chemical  form  was  sufficient  to  restore  their 
activity,  even  in  the  absence  of  either  bile  or  soap.  Analogous  results 
have  been  observed  from  other  causes  than  the  absence  of  bile;  thus 
some  of  the  pure  principles  of  the  purgatives  are  much  less  active  than 
the  crude  drugs  because  the  impurities  of  the  latter  alter  their  solubility. 
This  alteration  of  the  solubility  may  act  in  two  ways:  if  the  principle 
is  rendered  too  soluble,  it  may  be  absorbed  in  the  stomach  and  upper 
part  of  the  bowel,  and  therefore  fail  to  produce  purgation;  on  the 
other  hand,  it  may  be  rendered  so  insoluble  that  it  fails  to  come  into 
intimate  contact  with  the  bowel  wall,  and  therefore  does  not  irritate 
it.  The  effects  of  such  colloid  substances  as  the  bile  and  gums  is  to 
delay  the  absorption  of  soluble  substances  in  the  upper  part  of  the 
bowel  and  at  the  same  time  to  keep  the  insoluble  resins  in  suspension. 
Few  of  the  purgatives  have  any  appreciable  action  after  absorption, 
but  general  effects  may  be  produced  indirectly  from  their  intestinal 
action.  It  is  probable  that  reflexes  are  elicited  by  irritation  of  the 
bowel  analogous  to  those  discussed  under  skin  irritants,  but  in  addition, 
the  congestion  of  the  bowel  produced  by  its  activity  must  alter  con- 
siderably the  distribution  of  the  blood  in  the  body.  The  belief  in 
the  efficacy  of  a  purge  in  congestion  of  the  brain  may  thus  be  based 
on  a  true  "revulsive"  action;  for  the  dilatation  of  the  intestinal  vessels 
must  necessarily  lower  the  blood-pressure  and  thereby  lessen  the  blood 
supply  to  the  brain.  The  congestion  of  the  intestine  is  accompanied 
by  a  similar  condition  in  the  other  pelvic  organs,  and  the  purgatives 
therefore  often  cause  congestion  of  the  uterus,  with  excessive  men- 
strual flow,  or  in  the  case  of  pregnant  women,  abortion.  Lastly,  a 
certain  amount  of  fluid  is  withdrawn  which  would  otherwise  be 
excreted  by  the  urine,  which  is  found  to  be  proportionately  (liminished 
in  amount. 

1.  Mild  Aperients,  the  Castor  Oil  Group. 

Castor  Oil  (Oleum  Ricini)  resembles  olive  oil  in  most  respects,  but 
on  saponification  forms  ricinoleic  acid  instead  of  oleic  acid.  This 
acid  (Ci7ll;t2  (OII)(X)OII)  difl'ers  from  the  fatty  acids  obtained  from 
ordinary  oils  in  being  unsaturated  and  in  containing  a  hydroxyl  group. 
(\istor  oil  is  itself  a  bland,  n(,)n-irritating  fluid,  but  on  i)assing  into 
the  intestine  is  saponified  by  the  pancreatic  juice,  and  the  ricinoleates 
tluis  foniied  are  irritant  and  cause  purgation.    When  the  oil  is  saponified 


PURGATIVES  91 

and  the  free  acid  given  by  the  mouth,  the  effects  are  quite  different 
from  those  of  the  oil,  for  the  taste  is  acrid  and  unpleasant,  and  dis- 
comfort, nausea  and  vomiting  may  follow  its  ingestion  from  its  irritant 
action  on  the  stomach.  The  oil,  on  the  other  hand,  has  a  bland,  if 
unpleasant,  taste,  and  produces  no  effects  on  the  stomach.  Several 
other  esters  of  ricinoleic  acid  have  been  shown  by  Meyer  to  resemble 
the  glycerin  ester  (castor  oil)  in  their  purgative  effects. 

Castor  oil  is  absorbed  from  the  intestine  and  disappears  in  the  tissues 
in  the  same  way  as  an  ordinary  oil.  It  may  be  given  in  very  large 
quantities  without  producing  any  symptoms,  save  those  of  a  mild  laxa- 
tive. It  is  occasionally  used  as  an  emollient  to  the  skin,  and  has  been 
employed  as  a  solvent  for  application  to  the  eye.  The  harmless  nature 
of  castor  oil  is  shown  by  its  use  in  China  as  an  article  of  diet. 

In  the  beans  from  wliich  castor  oil  is  derived,  a  toxalbumiu  is  found,  which 
was  at  one  time  supposed  to  be  the  active  principle  of  the  oil.  (See  Ricin.) 
It  has  been  shown,  however,  that  the  oil  is  entirely  free  from  this  poison,  and 
that  its  action  is  due  solely  to  the  ricinoleate. 

Preparations. 

Oleum  Ricini,  a  fixed  oil  expressed  from  the  seed,  or  bean  of  Ricinus  com- 
munis.   Dose,  U.  S.  P.,  16  CO.  (4  fl.  drs.);  B.  P.,  1-8  fl.  drs. 

Mistura  Olei  Ricini  (B.  P.),  made  up  with  cinnamon  and  orange  flower 
water  by  means  of  mucilage,  1-2  fl.  oz. 

Castor  oil  is  difficult  to  take  owing  to  its  unpleasant  taste.  It  may  be  given 
alone,  in  an  emulsion  flavored  with  sugar  and  some  volatile  oil,  in  wine,  spirits, 
or  givcerin,  or  in  flexible  capsules. 

C^ (C6H40H)2, 

Phenolphthalein,  C6H4<      ^o  a  svnthetic  substance,  has  been 

CO 

used  of  late  years  as  a  mild  aperient.  It  is  very  insoluble  in  water 
and  is  not  irritant  when  applied  to  the  ordinary  mucous  membranes. 
In  the  bowel  it  is  dissolved  by  the  bile  and  alkali  and  develops  a  mild 
irritant  action  and  thus  accelerates  the  peristalsis  in  the  same  way 
as  castor  oil.  Most  of  the  phenolphthalein  administered  by  the  mouth 
is  not  absorbed  but  appears  in  the  stools.  A  small  amount  undergoes 
absorption  and  is  excreted  in  the  urine;  if  the  urine  is  alkaline  it  is 
colored  a  brilliant  pink.  Phenolphthalein  is  practically  not  poisonous 
when  ingested  intravenously  in  animals.  It  causes  a  mild  laxative  effect 
when  injected  subcutaneously,  and  this  arises  from  its  being  excreted 
into  the  bile  and  thus  carried  to  the  gut.  In  the  large  intestine  it  is 
reabsorbed  into  the  blood  and  again  carried  to  the  liver  and  returned 
to  the  gut.  It  therefore  acts  for  several  days  as  a  mild  aperient,  but 
as  it  is  gradually  eliminated  in  the  urine  and  stools,  the  action  passes 
off.  Tetrachlorphenolphthalein  acts  in  the  same  way  as  phenolph- 
thalein but  is  excreted  only  by  the  bile  when  injected  subcutaneously 
and  thus  acts  for  a  longer  time. 

I  Phenolphthaleinum  (B.  p.),  a  crystalline  powder,  white  or  grayish-white, 

"      soluble  in  600  parts  of  water  or  in  10  parts  alcohol.    The  solution  turns  red 

when  alkali  is  added.    Dose,  0.1-0.3  G.  (2-5  grs.)  in  powder,  pills,  or  capsules. 

It  has  been  injected  hypodermically  in  solution  in  olive  oil. 


92  SUBSTANCES  ACT  IXC  LOCALLY 

Sulphur  is  in  itself  an  inert  body,  but  while  much  the  greater  por- 
tion escapes  in  the  stools  unchanged  when  it  is  swallowed,  some  of  it 
forms  sulphides  in  the  nuicous  membrane  of  the  intestine,  and  these 
cause  irritation,  increased  j)eristalsis  and  a  soft,  formed  stool;  in  large 
quantities  it  has  caused,  in  some  instances,  more  severe  symptoms 
with  bloody  evacuations.  The  sulphides  form  some  hydrogen  sul- 
phide, which  gives  rise  to  eructation.  Some  10-20  per  cent,  of  the 
suli)hur  taken  by  the  mouth  is  absorbed  as  sulphide,  which  is  excreted 
to  a  small  extent  by  the  lungs,  giving  the  characteristic  disagreeable 
odor  to  the  breath,  and  to  a  much  larger  extent  by  the  urine  as  sulphates 
and  in  organic  combination.  In  one  experiment,  Presch  found  the 
urea  of  the  urine  considerably  increased  (10  per  cent.)  under  sulphur, 
and  Umbach  found  it  increased  by  pure  calcium  sulphide;  whether, 
as  this  would  suggest,  the  sulphides  augment  the  nitrogenous  waste 
as  a  general  rule,  can  only  be  determined  by  further  experiment.  It 
has  been  advised  in  a  number  of  constitutional  diseases  and  in  chlorosis 
and  joint  diseases. 

Applied  to  the  skin  in  ointment,  sulphur  appears  to  be  formed  in 
part  to  sulphide,  particularly  if  some  alkali  be  added;  the  sulphide 
is  destructive  to  animal  parasites  and  sulphur  ointment  has  therefore 
been  used  in  the  treatment  of  scabies,  but  has  been  supplanted  largely 
by  balsam  of  Peru. 

Preparations. 

S^dphur  Suhlimatum  (U.  S.  P.,  B.  P.),  Flowers  of  Sulphur,  sublimed  sulphur, 
and  Sulphur  Latum  (U.  S.  P.),  washed  Flowers  of  Sulphur,  form  fine  yellow 
powders  insoluble  in  water  and  very  slightly  soluble  in  alcohol. 

Stilphur  Pnecipilatum  (U.  S.  P.,  B.  P.),  Milk  of  Sulphur,  is  prepared  from  sul- 
phide of  calcium  by  precipitation  and  forms  a  fine,  almost  white  powder  with- 
out odor  or  taste,  insoluble  in  water,  and  only  verv  slightly  soluble  in  alcohol. 

Dose  of  all  three  preparations,  U.  S.  P.,  4  G.  (60  grs.) ;  B.  P.,  2()-60  grs. 

Unguentum  Sulphuris  (U.  S.  P.,  B.  P.),  formed  from  sublimed  sulphur, 
which  is  also  contained  in  the  Compound  Licjuoricc  Powder. 

Trochiscus  Sulphuris  (B.  P.)  contains  5  grs.  of  sulphur. 

Confertio  Sulphuris  (B.  P.),  00-120  grs. 

Crude  sublimed  sulphur  often  contains  arsenic,  but  the  B.  P.  i)reiiarati()n  is 
practically  free  from  it.  The  milk  of  sulphur  is  in  a  finer  state  of  division  than 
the  flowers,  and  is  said  to  be  a  somewhat  more  active  aperient. 

Glycerin. — When  glycerin  is  injected  into  the  rectum,  it  withdraws 
fluid  from  the  mucous  membrane  and  thus  causes  irritation,  ])ersistalsis, 
and  evacuation  of  the  bowels;  the  stool  is  of  ahnost  t)rdinary  con- 
sistency, and  no  pain  or  colic  is  felt  subseciuently,  nor  does  the  remedy 
cause  more  than  one  evacuation.  Glycerin  nuiy  be  injected  into  the 
rectum  for  this  purpose  (dose  2-5  c.c,  ^-1  teaspoonful),  but  a  more 
convenient  form  is  the  glycerin  sui)i)ositories,  Suppositoria  Glycerini, 
which  are  made  up  with  stearic  acid  and  sodium  carbonate,  I  .  S.  P., 
with  gelatin,  H.  P.  These  supi)ositories  are  fomul  not  to  keep  well, 
as  the  glycerin  tends  to  attrjict  moisture  and  then  es('a|)es;  to  avoid 
this  they  are  often  encased  in  ]»ara(lin,  wliirli  is  broken  ot!  immediately 


PURGATIVES  93 

before  they  are  inserted.  Glycerin  suppositories  are  used  in  constipation 
instead  of  the  ordinary  aperients.  Large  doses  of  glycerin  taken  intern- 
ally sometimes  cause  purgation,  but  it  is  not  a  reliable  remedy  when 
administered  in  this  way. 

Glycerin  in  large  quantities  is  poisonous,  whether  it  is  taken  by  the  mouth 
or  injected  h^ypodermically  or  intravenously.  It  is  true  that  no  case  of  gl3^cerin 
poisoning  in  man  is  known,  but  large  doses  are  fatal  to  animals  in  the  course 
of  a  few  hours.  The  chief  symptoms  are  restlessness,  agitation,  acceleration  of 
the  heart  and  respiration,  general  weakness,  tremor  and  convulsions,  which 
finall.y  end  in  somnolence,  coma,  and  death  from  failure  of  the  respiration. 
Glomerulonephritis  has  also  been  observed  in  animals.  Glycerin  is  absorbed 
rapidly  from  the  intestine,  and  undergoes  combustion  in  the  tissues,  only  a  very 
small  fraction  of  it  reappearing  in  the  urine. 


2.  The  Anthracene  Purgatives. 

A  number  of  purgatives,  Rhubarb,  Senna,  Aloes,  Cascara  and  Fran- 
(jula,  owe  their  activity  to  the  presence  of  irritant  anthracene  (CuHio) 
compounds,  only  a  few  of  which  have  been  isolated.  The  chemical 
examination  of  these  drugs  is  a  matter  of  great  difficulty,  as  they 
each  contain  several  active  principles  which  are  very  nearly  related 
to  each  other,  and  some  of  which  are  undoubtedly  the  products  of  the 
decomposition  of  more  complex  bodies. 

All  those  which  have  been  completely  isolated  hitherto  have  proved  to  be 
derivatives  of  anthraquinone, 

CH  CH  CH  CH  CO  CH 

/\  c  /\  c  /\  /\  c  /\  c  /\ 

HC/         \/         \/         \CH  HC/         \/         \/         \CH 

Hck         /\         /\         /CH  HC\         /\         A         /CH 
\/   C    \/    C    \/  \/    C    \/    C    \/ 

CH  CH  CH  CH  CO  CH 

Anthracene.  Anthraquinone. 

and  some  of  the  oxyanthraquinones  seem  to  be  widely  distributed.  Thus  all 
the  members  of  the  group  contain  Emodin  or  trioxymethylanthraquinone, 
(Ci4H4(CH3)  (011)302),  and  several  of  them  contain  Chnjsophanic  acid  or  dioxy- 
methylanthraquinone,  (Ci4H5(CH3)(OH)202).  In  addition,  a  number  of  other 
anthracene  bodies  occur  in  these  purgatives,  some  of  them  combined  with 
sugars  to  form  glucosides,  but  little  is  known  regarding  them  and  hardly  any 
of  them  are  definiteh'  established  as  pure  substances.  Among  the  names  applied 
to  these  ])odies  are  cathartin  or  cathartic  acid,  frangulin,  aloiu,  but  it  is  to  be 
noted  that  the  bodies  designated  bj'^  these  names  varj^  in  character  and  are 
alternate^  asserted  to  be  pure  principles  and  composite  mixtures  by  different 
investigators. 

None  of  the  pure  principles  are  as  satisfactory  in  their  action  as  the 
crude  drugs,  perhaps  because  they  are  less  soluble  in  the  intestine.  For 
example,  aloin  is  less  certain  in  its  efYects  than  aloes,  and  it  seems  to 
be  indisputable  that  the  crystalline  aloin  itself  is  inactive  in  the  bowel, 
but  is  there  changed  under  certain  conditions  to  an  amorphous  com- 


94  SUBSTANCES  ACTING  LOCALLY 

pound  which  has  irritant  effects.  The  presence  of  bile  in  the  intestine 
is  not  necessary  to  elicit  the  action  of  this  group,  except  perhaps  in  the 
case  of  rhubarb. 

The  absorption  of  these  bodies  has  not  been  satisfactorily  deter- 
mined in  most  cases.  The  urine  is  rendered  yellow  after  rhubarb  and 
senna,  owing  to  the  absorption  and  excretion  of  chrysophanic  acid, 
but  it  is  questionable  whether  the  more  active  principles  pass  into  the 
urine  in  appreciable  amounts.  When  aloin  is  injected  subcutaneously 
or  intravenously,  it  is  excreted  for  the  main  part  into  the  bowel,  and 
there  produces  irritation  and  catharsis.  The  yellow  pigment  of  the 
urine  after  rhubarb  and  senna  becomes  a  purple  red  on  the  addition  of 
alkalies;  the  milk  and  skin  also  are  said  to  assume  a  yellowish  tinge 
from  the  presence  of  chrysophanic  acid. 

In  the  rabbit  aloin  seldom  causes  purgation,  and  is  excreted  by  the 
kidney  in  considerable  quantity,  especially  when  injected  hypoder- 
mically.  In  passing  through  this  organ  it  causes  marked  irritation 
and  epithelial  necrosis,  which  often  proves  fatal  in  a  few  days.  No 
irritation  of  the  kidney  occurs  in  man,  the  dog,  or  the  cat  after  aloin. 
Injected  intravenously  in  animals,  aloin  induces  powerful  contrac- 
tions of  the  uterus,  apparently  from  direct  action  on  the  organ.  The 
same  effect  probably  occurs  when  it  is  absorbed  from  the  alimentary 
tract,  and  its  use  is  not  advisable  during  pregnancy  or  menstruation. 

Rhubarb  contains  a  considerable  amount  of  tannic  acid,  which  acts 
as  an  astringent  and  therefore  tends  to  cause  constipation  after  the 
evacuation  of  the  bowels.  It  is  not  well  tolerated  in  some  cases,  its 
administration  being  followed  by  nausea,  headache  and  giddiness, 
more  rarely  by  skin  eruptions  of  different  kinds.  Senna  preparations 
are  generally  found  to  have  a  greater  tendency  to  produce  griping 
than  the  other  members  of  this  series. 

Preparations. 

U.  S.  P. — Rheum,  rhubarb,  the  rhizome  of  Rheum  officinale.     1  G.  (15  grs.). 

ExTRACTUM  Rhei,  0.25  G.  (4  grs.). 

Fluidextradum  Rhei,  1  c.c.  (15  mins.). 

P1LUL.E  Rhei  Composite  (aloes,  myrrh,  and  oil  of  peppermint),  2  jiills. 

PuLVis  Rhei  Compositus  (Gregory's  Powder)  contains  magnesia  and  ginger. 
Dose,  2  G.  (30  grs.). 

Tindura  Rhei,  4  c.c.  (1  fl.  dr.). 

Tindura  Rhei  Aromatica  (contains  several  volatile  oils),  2  c.c.  (30  mins.). 

Syniptis  Rhei  1  ,^        „  /o  a    j     \ 

Syrupus  1{mki  AuoMATicus  i  ^os^'  8  ;'-^-  (^  fl-  ^^•^■)- 

B.  P. — Rhei  Rhizoma,  rhubarb,  the  rliizome  of  Rheum  palmatum;  3-10  grs. 
for  repeated  uiliiiinislratioii;  for  a  single  administration,  15-30  grs. 

PiLULA  1{hei  CoMi'OsrrA  (contains  rhubarb,  aloes,  myrrh,  and  oil  of  pepper- 
mint), 4-8  grs. 

Pi'i.vis  HuEi  (.'o.Mi'Osrrirs  (Gregory's  Powder)  contains  rlmharb,  light 
magnesia  and  ginger,  10-GO  grs. 

'J'lNCTiKA  Hmki  Comi'o.sita,  formed  from  rhubarb,  cardamom  and  cori- 
ander, ',-1  II.  tlr.  for  repeated  administratioi?;  2^  fl.  drs.  for  a  single  admin- 
istration. 

Syrupus  Rhei,  i-2  11.  drs. 


PURGATIVES  95 

U.  S.  p. — Senna,  the  leaflets  of  Cassia  acutii'oiia  (Alexandria  Senna),  and 
of  Cassia  angustifolia  (India  Senna). 

Fliddextr actum  Sennce,  2  c.c.  (30  niins.)- 

Infusum  Senn^  Compositum  (Black  Draught)  contains  senna,  manna, 
magnesium  sulphate  and  fennel,  120  c.c.  (4  fl.  oz.). 

Syrupus  Senn^,  4  c.c.  (1  fl.  dr.). 

Senna  is  also  contained  in  the  compound  syrup  of  sarsaparilla  and  in  tlie 
compound  liquorice  powder. 

Senna  is  often  administered  as  a  simple  infusion,  senna  tea,  a  teaspoonful 
of  the  leaves  being  used  in  a  cupful  of  water. 

B.  P.— Senna,  the  dried  leaflets  of  Cassia  acutifolia  (Alexandrian  senna),  and 
of  Cassia  angustifolia  (Tinnevelly  senna). 

Syrupus  Sennce,  ^-2  fl.  drs. 

Infusum  Senn^,  ^-1  fl.  oz.;  as  a  draught,  2  fl.  oz. 

MiSTURA  Senn^  Composita  (Black  Draught),  formed  from  magnesium  sul- 
phate, liquorice,  compound  tincture  of  cardamom,  aromatic  spirit  of  ammonia, 
and  infusion  of  senna,  ^-2  fl.  oz. 

CoNFECTio  Senn^,  formed  of  senna,  coriander,  figs,  tamarinds,  cassia, 
prunes,  liquorice,  and  sugar,  60-120  grs. 

U.  S.  P.— Aloe,  the  inspissated  juice  of  the  leaves  of  several  species  of  aloe. 

Aloe  Purificota,  aloes  from  which  insoluble  impurities  have  been  removed, 
0.25  G.  (4  grs.). 

Aloinum,  a  neutral  principle  obtained  from  aloes,  0.065  G.  (1  gr.). 

ExTRACTUM  Aloes,  0.12  G.  (2  grs.). 

Pilule  Aloes,  2  pills. 

Pilule  Aloes  et  Ferri,  2  pills. 

TiNCTURA  Aloes,  2  c.c.  (30  mins.). 

Aloes  is  also  contained  in  compound  rhubarb  pill,  compound  extract  of 
colocynth,  and  compound  tincture  of  benzoin. 

B.  P. — Aloe,  the  dried  juice  of  Aloe  chinensis  and  other  species,  2-5  grs. 

Aloinum,  \--2  grs. 

ExTRACTUM  Aloes,  1-4  grs. 

PiLULA  Aloes,  4-8  grs. 

PiLULA  Aloes  et  Ferri,  4-8  grs. 

PiLULA  Aloes  et  Asafetid.^;,  4-8  grs. 

Decodum  Aloes  Compositum  (aloes,  myrrh,  potassium  carbonate,  liquorice, 
compound  tincture  of  cardamom),  \-2  fl.  oz. 

Aloes  is  also  contained  in  the  compound  extract  of  colocynth,  compound 
-colocynth  pill,  pill  of  colocynth  and  hyoscyamus,  compound  tincture  of  benzoin 
and  compound  rhubarb  piU. 

U.  S.  P.— Frangula,  Buckthorn,  the  bark  of  Rhamnus  frangula. 

Fluidextr actum  Frangula^,   1  c.c.   (15  mins.). 

U.  S.  P.~Rhamnus  Purshiana,  Cascara  sagrada,  the  bark  of  Rhamnus 
Purshiana. 

Extractum  Rhamni  Purshianw,  0.25  G.  (4  grs.). 

Fludextractum  Rhamni  Purshianw  Aromaticum,  1  c.c.  (15  mins.). 

Fluidextractum  Rhamni  Purshiana,  1  c.c.  (15  mins.). 

B-  P.— Cascara  Sagrada,  the  dried  bark  of  Rhamnus  Purshianus. 

Extractum  Cascaroi  Sagradce  Siccum,  2-8  grs. 

Extractum  Cascara  Sagradce  Liquidum,  ^-1  fl.  dr. 

Syrupus  Cascarw  Aromaticus,  \--2  fl.  drs. 

Two  artificial  compounds  of  oxyanthraquinone  have  recently  been  intro- 
duced under  the  name  of  jmrgatin  and  exodin.  They  are  quite  insoluble  in 
water  and  tasteless  but  are  decomposed  in  the  intestine  and  act  there  like  the 
other  purgatives.  Purgatin  colors  the  urine  red  and  has  some  tendency  to  irri- 
tate the  kidneys.  Dose,  0.5-1 .0  G.  (8-15  grs.),  in  friable  tablets  or  suspended 
in  water.  These  bodies  have  no  advantages  o\'er  the  natural  purgatives  and 
the  possibility  of  their  inducing  nephritis  renders  their  use  inadvisable. 


96  SUBSTANCES  ACTING  LOCALLY 

Of  tlifst'  iiuiiuTous  prej)arati()ns,  the  most  extensively  preseribed  are 
the  pills.  The  fluid  preparations  have  an  unpleasant,  bitter  taste,  and 
are  therefore  less  used,  unless  when  disguised  by  the  addition  of  sugar 
or  volatile  oils.  The  syrups  of  rhubarb  and  senna  are  often  admin- 
istered to  children,  and  the  confection  of  senna  and  the  compound 
liquorice  powder  are  also  pleasant,  easily  taken  preparations.  The 
compound  infusion  or  mixture  of  senna  and  the  compound  rhubarb 
powder  are  old  and  tried  preparations,  in  which  the  virtues  of  the 
vegetable  purgative  are  combined  with  those  of  a  saline  cathartic  and 
antacid  respectively;  they  are  both  possessed  of  a  harsh,  unpleasant 
taste.  Frangula  is  comparatively  rarely  used,  but  the  fluid  extract  of 
cascara  sagrada,  which  is  practically  identical  with  it,  is  a  very  popular 
remedy  in  habitual  constipation. 

3.  The  Jalap  and  Colocynth  Group. 

The  third  group  of  the  vegetable  purgatives  comprises  a  number  of 
resinous  glucosides  and  acids,  whose  more  intimate  chemical  structure 
is  unknown,  though  a  number  of  them  appear  to  be  nearly  related 
chemically,  so  that  it  is  possible  that  they  all  contain  a  common  radicle 
like  the  members  of  the  anthracene  group. 

Jalap  resin  contains  two  anhj'dride  glucosides,  Convolvulm  and  Jalapin, 
the  latter  only  in  ver}^  small  quantity.  Scammony  consists  very  largely  of 
Jalapin.  Elaterium  contains  elaterin,  a  very  powerful  purgative  of  which  little 
is  known.  Podophj'llum  contains  two  isomeric  principles,  Podophyllotoxin  and 
Picropodophyllin.  Gamboge  owes  its  activity  to  Camhogic  acid,  which,  how- 
ever, is  insoluble,  and  seldom  acts  unless  it  is  accompanied  bj'  the  inactive 
bodies  of  the  crude  drug.  Colocynthin  is  a  glucoside  occurring  in  the  colocynth 
fruit,  and  forms  Colocynthem  and  sugar  when  treated  with  acids;  colocynthein 
is  said  to  be  even  more  irritant  than  colocynthin.  FAionj^mus  owes  its  activity 
to  a  resinous  glucoside,  Euonymin.  Croton  oil  contains  a  resinous  anhydride^ 
dissolved  in  an  inactive  oil.  The  seeds  from  which  the  oil  is  obtained  contain  a 
poisonous  protein,  but  this  is  not  contained  in  the  oil.  Many  other  {)lants  con- 
tain similar  resinous  purgative  substances,  and  some  of  these  are  used  as  remedies 
to  some  extent,  but  so  little  is  known  of  their  properties  and  they  are  so  seldom 
employed  that  they  may  be  omitted  here. 

Action. — These  substances  arc  in  general  much  more  powerful  than 
any  of  the  other  purgatives,  and  are  therefore  classed  together  as  the 
drastic  purgatives  or  hydragogue  cathartics.  Tn  small  (piantities  they 
cause  evacuation  more  rapidly  than  the  anthracene  purgatives,  and 
in  somewhat  larger  doses  produce  profuse  watery  stools  with  much 
pain  and  often  tenesmus.  In  cases  of  poisoning,  the  bowel  undergoes 
acute  inHanuiuition,  and  blood  is  passed  in  the  stools,  which  often 
contain  shreds  of  ei)ithelium  from  the  walls.    The  irritant  action  is  not 

'  The;  actii)M  of  croton  oil  is  often  staled  to  ho  due  to  crotonoknc  acid  derived  from  the 
oil  in  the  sanu;  way  as  ricinoleic  acid  is  obtained  by  tlic  saponification  of  castor  oil.  This 
is  incorrect,  however,  the  croton  resin  which  is  the  active  principle  of  croton  oil  havinK  no 
relation  to  the  oil  in  which  it  is  dissolved.  Several  other  plants  contain  similar  i)rincii)les, 
e.  (].,  Jatropha  cwrcas,  which  bears  the  l^arbadoes  nuts,  or  purj^inf?  nuts,  and  Garcia 
nutans  and  several   species  of  Omphalea  (Cash). 


PURGATIVES  97 

confined  to  the  bowel  apparently,  for  their  administration  is  some- 
times followed  by  uneasiness  in  the  stomach,  and  occasionally  by  nausea 
and  vomiting.  On  the  other  hand,  moderate  quantities  are  said  not  to 
induce  colic  so  frecpiently  as  some  of  the  anthracene  purges. 

Several  of  these  resinous  purges  are  irritant  to  the  skin  and  especially  to 
■  the  mucous  membranes  of  the  eye,  nose,  and  throat.  Thus  jalap,  podophyl- 
lum and  colocynthin  all  cause  pain  and  irritation  when  they  are  applied  to 
the  nostrils  in  fine  powder,  and  croton  oil  and  podophyllum  have  been  used  as 
skin  irritants. 

The  presence  of  bile  in  the  intestine  increases  the  purgative  action  of  almost 
all  these  bodies,  and  in  fact,  seems  essential  for  the  action  of  most  of  them. 

Podophyllotoxin  and  colocynthin  cause  purgation  when  injected  subcu- 
taneously;  this  is  probably  owing  to  their  excretion  into  the  bowel,  as  the 
former  has  been  detected  in  the  fseces  after  this  method  of  administration.  Podo- 
phj'Ilotoxin  causes  glomerular  nephritis  and  haemorrhages  into  various  organs 
when  administered  hypodermically  or  intravenously  in  large  quantities,  and 
when  added  to  blood  in  a  test-tube,  it  causes  the  formation  of  methsemoglobin 
in  the  corpuscles.  It  has  been  said  to  have  a  depressant  action  on  the  central 
nervous  system,  but  this  is  probabl}^  a  result  of  the  shock  and  haemorrhage 
produced  by  its  intestinal  action.  Colocynthin  is  said  to  cause  renal  inflam- 
mation when  applied  subcutaneously  or  taken  internall}^,  and  even  when  the 
powder  is  inhaled  during  its  manufacture.  Jalapin  and  convolvulin  given  by 
the  mouth  cannot  be  found  in  the  fseces  or  urine,  and  are  therefore  supposed  to 
undergo  partial  or  complete  oxidation  in  the  body.  Convolvulin  is  found  in 
the  urine,  however,  when  it  is  injected  intravenously,  and  no  purgation  follows 
this  method  of  administration;  so  that  it  is  probable  that  convolvulin  is  decom- 
posed in  the  bowel  when  it  is  administered  internally.  Euonjanin  has  the  same 
effect  on  the  heart  as  digitalis,  and  will  be  mentioned  along  with  it,  although 
it  has  a  mild  purgative  action  and  is  used  chiefly  as  an  aperient. 

Preparations. 

Colocynthis  (U.  S.  P.),  Colocynthidis  Pulpa  (B.  P.),  colocynth,  the  fruit  of 
Citrullus  Colocynthis  deprived  of  its  rind. 

Extradum  Colocynthidis  (U.  S.  P.),  0.03  G.  {\  gr.). 

ExTRACTUM  Colocynthidis  Compositum  (U.  S.  P.,  B.  P.)  (containing  colo- 
cynth, aloes,  scammony  and  cardamom),  0.5  G.  (7^  grs.)  (B.  P.,  2-8  grs.). 

Pilule  Cathartic.e  Composite  (U.  S.  P.)  (compound  extract  of  colocynth, 
jalap,  gamboge,  and  calomel),  2  pills. 

PiLULiE  Cathartic.e  Vegetabiles  (U.  8.  P.)  (contain  compound  extract 
of  colocjaith,  jalap,  leptandra,  podophyllum,  Iwoscyamus  and  oil  of  pepper- 
mint), 2  pills. 

Pilula  CoLOcyNTHiDis  CoMPOsiTA  (B.  P.)  (colocynth,  aloes,  scammony 
resin,  potassium  sulphate  and  oil  of  cloves),  4-8  grs. 

Pilula  Colocynthidis  et  Hyoscyami  (B.  P.)  (compound  pill  of  colocynth 
and  extract  of  hyoscyamus),  4-8  grs. 

Oleum  Tiglii  (U.  S.  P.),  Oleum  Crotonis  (B.  P.),  a  fixed  oil  expressed  from 
the  .seed  of  Croton  Tighuni.    0.05  c.c.  (1  niiii.). 

Podophyllum  (U.  S.  P.),  Podophylli  Rhizoma  (B.  P.),  the  rhizome  and  roots 
of  Podophyllum  peltatum. 

Fluidextradum  Podophylli  (U.  S.  P.),  0.5  c.c.  (8  mins.). 

Resina  Podophylli  (U.  8.  P.,  B.  P.),  5-15  mgs.  (I'.-i  gr.);  B.  P.,  i-1  gr. 

Tinctura  Podophylli  (B.  P.),  5-15  mins. 

Podophyllin  varies  considerably  in  composition,  and  ought  to  be  avoided. 

Jalapa  (U.  8.  P.,  B.  P.),  the  tuberous  root  of  Exogouium  Purga  (U.  8.  P.), 
of  Ipomoea  Purga  (B.  P.).     0.3-1  G.     (5-15  grs.). 
7 


98  SUBSTANCES  ACTING  LOCALLY 

Resina  Jalap/E  (U.  S.  P.,  B.  P.),  0. 125  G.  (2  grs.);  2-5  grs.,  B.  P. 

PuLVis  Jalap.e  Compositus  (U.  S.  p.,  B.  P.)  contains  jalap  and  bitartrate 
of  potassium.    2  G.  (30  grs.);    10-60  grs.,  B.  P. 

Scammonise  Radix  (B.  P.),  Scanunony  root,  the  dried  root  of  Convolvulus 
Scanmionia. 

Scammonium  (U.  S.  P.)  Scammonice  Resina  (B.  P.),  0.2  G.  (3  grs.);  4-8  grs., 
B.  P. 

Scannnony  is  also  conlained  in  the  conipound  colocynth  preparations. 

Euonymus  (U.  S.  P.),  Euonymi  Cortex  (B.  P.),  Wahoo,  the  dried  root-bark 
of  Euonymus  atropurpureus. 

Eairachim  Euonymi  (U.  S.  P.),  0. 125  G.  (2  grs.).     (B.  P.),  1-2  grs. 

Elaterinum  (U.  S.  P.),  C20H28O6,  a  neutral  principle  obtained  from  elaterium, 
a  suljstauce  deposited  by  the  juice  of  the  fruit  of  Ecballium  Elaterium 
(squirting  cucumber).    5  mgs.  (iV  gr.). 

TriUimtio  Elaterini  (U.  S.  P.)  (one  part  elaterin  in  9  parts  sugar  of  milk), 
0.03  G.  (^gr.). 

Cambogia  (U.  8.  P.  ),  Gamboge,  a  gum  resin  obtained  from  Garcinia  Han- 
burii.    Dose,  0.125  G.  (2  grs.). 

The  resinous  purgatives  are  generally  administered  in  i^iil  form; 
very  frequently  two  or  more  are  combined  in  one  pilt,  or  they  may  be 
prescribed  along  with  extract  of  belladonna  or  hyoscyamus,  or  with  a 
drop  of  some  carminative  oil  or  resin,  to  prevent  the  pain  and  griping 
which  often  accompanies  their  action.  Croton  oil  is  often  given  in  a 
pill  made  up  with  breadcrumb,  or  a  single  drop  maj''  be  given  on  a 
lump  of  sugar  or  in  solution  in  castor  oil.  The  importance  of  these 
purgatives  is  much  less  than  it  was  formerly,  and  several  of  them  are 
very  seldom  used;  the  most  important  are  colocynth,  podophyllum, 
croton  oil,  and  jalap.  In  large  doses  they  act  rapidly,  with  the  excep- 
tion of  podophylhun,  which  induces  purgation  very  slowly  (10-20 
hours). 

Therapeutic  Uses  of  the  Purgatives, — The  purgatives  are  employed 
to  cause  evacuation  of  the  bowel  when  for  any  reason  its  peristalsis  is 
slow.  In  the  choice  of  a  purgative,  the  advantages  of  the  vegetable 
purgatives  must  be  weighed  against  those  of  the  saline  cathartics  and 
of  the  mercurial  preparations.  In  ordinary  constipation  of  short 
standing,  in  which  the  peristalsis  may  merely  seem  somewhat  more 
sluggish  than  usual,  the  milder  laxatives  are  prescribed  —  castor  oil, 
sulphur,  senna,  rhubarb,  aloes,  frangula,  or  cascara  sagrada.  The 
first  two  cause  least  disturbance  of  the  bowel,  but  are  disagreeable  to 
take,  and  are  less  commonly  prescribed  for  adults  than  rhubarb  or 
cascara,  or  small  doses  of  colocynth  or  podophyllum.  In  children  or 
in  debility  in  adults,  senna  and  castor  oil  are  frequently  used;  sulphur 
is  often  given  along  with  magnesia  in  constipation  in  children,  and  in 
haMuorriioids  in  which  it  is  often  beneficial,  not  owing  to  any  specific 
action  on  the  ha'inorrhoids  but  because  it  renders  the  stools  softer 
and  less  liable  to  cause  irritation  mechanically. 

In  chronic  constipation  which  cannot  be  controlled  by  hygienic 
measures,  or  by  the  use  of  a  s])ecial  dietary  such  as  fruits,  or  coarse 
meal,  and  where  the  intestine  has  M])parently  taken  on  a  sluggish 
habit,  rhubarb,  cascara,  aloes,  phcnolphthalcin,  or  colocynth  may  be 


r 


PURGATIVES  99 


ordered,  but  the  saline  cathartics  often  prove  more  satisfactory. 
Rhubarb  tends  to  cause  some  constipation  after  its  laxative  effects, 
but  is  often  used  in  these  cases,  as  it  possesses  some  bitter  stomachic 
action,  which  compensates  for  its  astringent  after-effects.  This  bitter 
action  is  often  given  to  the  other  purgatives  by  the  addition  of  gentian, 
nux  vomica,  or  cinchona.  In  obstinate  constipation,  in  which  the 
bowel  contains  hard  ftecal  masses,  the  milder  purgatives  often  provoke 
griping  without  relieving  the  condition,  and  in  these  cases  larger  doses 
of  colocynth,  jalap,  podophyllum,  or  croton  oil  are  used,  along  with 
some  of  the  extracts  of  the  atropine  group  or  with  a  carminative  oil. 
They  may  be  prescribed  along  with  some  of  the  saline  cathartics,  as 
in  the  compound  infusion  of  senna  or  the  compound  powder  of  jalap. 

Croton  oil  is  used  especially  where  the  drug  is  required  to  be  of 
small  bulk  and  the  administration  is  attended  with  special  difficulty; 
thus  in  unconsciousness  or  mania,  one  or  two  drops  may  be  given  on 
sugar.  In  lead  colic,  croton  oil  is  said  to  act  more  rapidly  and  efficiently 
than  the  others. 

In  some  forms  of  diarrhoea  constant  irritation  seems  to  be  kept  up 
by  the  presence  of  irritants  in  the  bowel,  and  the  indications  are  the 
removal  of  these  by  a  purge  rather  than  the  administration  of  astrin- 
gents. Castor  oil,  senna  and  rhubarb  are  especially  adapted  for  this 
purpose;  the  first  two  because  they  increase  the  irritation  of  the  bowel 
less  than  the  others,  the  latter  because  of  its  subsequent  astringent 
action. 

A  purgative  is  often  administered  as  a  preliminary  in  the  treatment 
of  malaria,  syphilis  and  other  conditions,  and  seems  to  have  beneficial 
effects,  although  these  are  difficult  to  explain.  In  the  beginning  of 
acute  fevers  also,  a  purge  is  often  useful,  perhaps  through  the  conges- 
tion of  the  bowel  withdrawing  the  blood  from  the  rest  of  the  body,  or 
through  the  removal  of  poisonous  substances  formed  by  the  decom- 
position of  the  intestinal  contents.  In  congestion  of  the"^  brain  and  in 
high  blood-pressure  a  purgative  is  often  administered  with  good 
effects,  which  may  also  be  attributed  to  the  accumulation  of  blood  in 
the  mesenteric  circulation,  to  the  actually  lessened  bulk  of  the  blood, 
and  perhaps  to  some  action  analogous  to  counter-irritation  of  the  skin. 
For  these  purposes  a  sharp  purge  is  generally  used,  such  as  croton  oil 
or  some  other  of  the  jalap  and  colocynth  series. 

The  more  powerful  purgatives,  especially  elaterin,  were  formerly 
largely  used  to  remove  fluid  from  the  body  in  cases  of  dropsy  or 
oedema,  and  they  were  generally  prescribed  along  with  the  saline 
cathartics  for  this  purpose.  Other  means,  such  as  diuretics,  are  gen- 
erally preferred  now  from  a  fear  that  the  violent  purging  may  weaken 
the  patient,  but  good  results  are  often  obtained  by  means  of  this 
treatment,  especially  as  a  preliminary  to  the  use  of  digitalis. 

The  s})ecific  action  of  aloes  on  the  uterus,  perhaps  aided  by  the 
congestion  of  the  pelvic  organs  from  its  purgative  effects,  has  led  to 
its  use  in  amenorrhoea;  it  is  generally  administered  along  with  iron, 
which  improves  the  condition  of  the  blood. 


100  SUBSTANCES  ACTING  LOCALLY 

The  purjies  act  as  intestinal  disinfectants  by  removing  the  micro- 
organisms mechanically,  though  the  vegetable  purges  are  less  used 
for  this  purpose  than  calomeh  A  purgative  is  administered  to  remove 
poisons  in  the  intestine  when  they  have  pased  beyond  the  stomach 
or  when  they  are  excreted  into  the  bowel. 

Purgatives  are  contra-indicated  in  conditions  of  acute  intestinal 
irritation,  and  during  menstruation  and  pregnancy,  owing  to  the  con- 
gestion of  the  pelvic  organs,  which  may  lead  to  an  excessive  flow  in  the 
one  case  and  to  abortion  in  the  other;  aloes  is  especially  dangerous 
in  these  conditions.  In  collapse,  asthenia  and  anaemia,  powerful  pur- 
gatives are  contra-indicated,  owing  to  the  irritation  they  produce.  In 
h.emorrhoids,  aloes  is  often  said  to  do  harm  by  increasing  the  conges- 
tion of  the  rectum,  and  powerful  purges  are  injurious  from  the  straining 
they  cause,  but  if  constipation  is  present,  a  mild  purgative  is  beneficial. 
In  all  those  conditions,  if  a  purgative  is  required,  either  castor  oil, 
senna,  or  rhubarb  ought  to  be  chosen. 

Repeated  attempts  have  been  made  to  produce  e\-acuation  of  the  bowels 
by  substances  injected  subcutaneously,  but  the  ordinary  purgatives  are  not 
suitable  as  they  cause  intense  pain  at  the  seat  of  injection.  Phj'sostigmine 
has  been  employed  frequently,  and  more  recently  tetrachlorphenolphthalein 
has  been  used  by  Abel  and  Rowntrce  in  solution  in  oil. 

Another  method  by  which  the  purgatives  may  be  administered  is  in  enema. 
The  addition  of  purgatives,  such  as  castor  oil,  and  of  bile  to  the  ordinary 
cnemata  has  been  practised  for  many  j'^ears,  and  small  (juantities  of  other 
purgatives  have  occasionally  been  emploj^ed  in  oil  or  glycerin. 

Bibliography  of  the  Purgatives. 
Purgative  action  in  general. 

Brimton.     Practitioner,  xii,  p.  342. 

Stadclmann.  Berliner  klin.  Woeh.,  189G,  p.  ISl.  Archiv.  f.  exp.  Path.  u.  Pharm., 
xxxvii,  p.  352. 

Wood.     Amcr.  Journ.  of  Mod.  Sciciipos,  Ix,  p.  75. 

Hiller.     Ztschr.  f.  klin.  Med.,  iv,  p.  481. 

Kohlstock.     Charit6-annalen,  xvii,  p.  283. 

Magnus.    Ergebnisse  dor  Physiologic,  ii,  (2),  p.  601.     (Literature.) 

Tappeiner.     Arch,  internat.  de  Pharmacodyn.,  x,  p.  80. 

Dixon.    Brit.  Med.  Journ.,  Oct.  18,  1902. 

Castor  oil  group. 

Meyer.     Arch.  f.  cxp.  Path.  u.  Phann.,  xxviii,  p.  145:    xxxviii,  p.  330. 

Mu(jnus.    Arch.  f.  d.  ges.  Piiys.,  cxxii,  p   201. 

Ahcl  and  Rowntree.    Journ.  of  Pharmacology,  i,  p.  231  (phenoli)htlKilfiii). 

Preach.     Virchow's  .Vrchiv,  cxix,  p.  148  (sulphur). 

Umhach.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxi,  p.  16G  (sulphur). 

Hcffter.     Ibid.,  li,  p.  175  (sulphur). 

Taegen.     Ii)id.,  Ixix.  p.  203  (.sulphur). 

Anthracene  purgatives. 

.\|.()IN.     Mcijir.     .Arch.  f.  exp.  Path.  u.   Phann.,  xxviii,  p.   ISO. 
Kohn.     Berl.  klin.  Woch.,  1882.  p.  r.8. 
Mnrsel.      Arch.   f.   exp     l*a(li.   u.    I'liarin.,   xi\,    p.   .SU). 
linselnwnl.     Il)id.,  xliii,  p.  274. 


SALINE  CATHAPTICS  .101 

Tschirch.     Bericht.  d.  deutsch.  pharmaceut.  Gcsellsch.,   1898,   p.   174. 
Senna.     Stockman.    Arch.  f.  exp.  Path.  u.  Pharm.,  xix,  p.  117. 
Magnus.     Arch.  f.  d.  ges.  Phys.,  cxxii,  p.  251. 
Vieth.     Miinch.  med.  Woch.,  1901,  No.  35. 
Frangula.     Baeumker.     Inaug.  Diss.,  Gottingen,  1880. 
Weyl.     Pfluger's  Archiv,  xliii,  p.  367. 

Jalap  and  Colocynth  Series. 

Podophyllum.     Podwyssotzki.    Arch.  f.  exp.  Path.  u.  Pharm.    xiii,  p.  29. 

Neuberger.    Ibid.,  xxviii,  p.  32. 

Disque.     Inaug.  Diss.,  Rostock,  1913. 

Jalap.    J.  Muller.    Inaug.  Diss.,  Dorpat,  1885. 

Scher.     Inaug.  Diss.,  Dorpat,  1895;    Virchow-Hirsch  Jahresber.,  1895,  p.  380. 

Colocynth.    Padtberg.    Arch.  f.  d.  g.  Physiol.,  cxxxiv,  p.  627. 

Elaterium.     Kohler.     Virchow's  Archiv,  xlix,  p.  408. 


K.     SALINE  CATHARTICS. 

Dilute  solutions  of  such  salts  as  the  chlorides,  iodides,  and  bromides 
of  the  alkalies  are  absorbed  rapidly  from  the  alimentary  canal,  but 
some  of  the  other  salts  of  these  metals  apparently  permeate  the  epithe- 
Hum  with  greater  difficulty,  and  their  solutions  therefore  remain  unab- 
sorbed  for  a  longer  time  in  the  intestine.  The  contents  of  the  intestine 
and  the  stools  thus  contain  more  fluid  than  usual  and  these  salts  are 
known  as  the  saline  cathartics.  The  chief  salts  of  sodium  and  potassium 
which  have  this  intestinal  action  are  the  sulphates,  phosphates,  tartrates 
and  citrates;  less  known  ones  are  the  malates  and  ferrocyanides. 

In  these  effects  the  acid  constituent,  or  anion,  is  obviously  the  chief 
factor,  for  the  same  base,  or  cation,  is  present  in  readily  absorbed  salts 
such  as  the  chlorides.  And  no  pronounced  dift'erences  between  the 
action  of  chlorides  and  sulphates  are  observed,  unless  the  salt  can  be 
given  in  large  quantities,  as  is  possible  in  the  case  of  the  salts  of  the 
alkalies.  The  eflects  of  the  sulphate  and  hydrochlorate  of  morphine, 
for  example,  may  be  taken  as  identical,  because  the  anion  is  present 
in  so  small  amount  as  to  be  practically  inert. 

The  anion  of  a  salt  may  also  fail  to  be  taken  up  readily  by  the  bowel; 
for  example,  magnesium  chloride  is  absorbed  slowly  although  other 
chlorides  permeate  rapidly,  and  magnesium  salts  thus  act  as  purgatives 
in  the  same  way  as  sulphates.  When  both  ions  are  slowly  absorbed, 
as  in  the  case  of  magnesium  sulphate,  the  cathartic  action  is  naturally 
more  powerful  than  when  only  one  has  this  character. 

The  chief  saline  cathartics  used  in  therapeutics  are  the  sulphate  of 
sodium  (Glauber's  salt),  the  sulphate  of  magnesium  (Epsom  salt), 
the  double  tartrate  of  sodium  and  potassium  (Rochelle  salt)  and  the 
phosphate  of  sodium.  In  addition  the  oxide  and  carbonate  of  magnesium 
have  some  purgative  action  from  being  formed  into  soluble  salts  in  the 
stomach  and  intestine.  But  besides  these,  many  other  salts  are  slowly 
absorbed  and  might  therefore  be  used  for  this  purpose.  Thus  the 
sulphates,  citrates,  or  tartrates,  of  any  of  the  alkalies  or  of  the  non- 
poisonous  alkaloids  might  be  used  for  this  purpose,  provided  they  are 
soluble,  and  any  of  the  magnesium  salts  might  be  used  in  the  same  way. 


102  SUBSTANCES  ACTING  LOCALLY 

Symptoms. — The  external  application  of  solutions  of  the  saline 
cathartics  has  the  same  cft'ect  as  that  of  any  other  indifferent  salts, 
such  as  sodium  chloride. 

Most  of  the  catiiartics  have  a  harsh,  bitter,  unpleasant  taste,  and 
when  taken  in  concentrated  solution,  may  induce  some  nausea,  partly 
from  the  taste,  and  partly  from  the  "salt-action"  on  the  stomach, 
which  they  possess  like  other  soluble  bodies.  Dilute  solutions,  however, 
provoke  no  such  symptoms,  but  after  one  or  two  hours  induce  a  profuse 
watery  evacuation  of  the  bowels.  This  is  sometimes  preceded  by  some 
pain  and  griping,  but  these  are  not  nearly  so  frequent  or  so  severe  as 
after  the  vegetable  purgatives.  Not  infrequently  the  urine  is  increased 
in  amount  afterward,  or  it  may  be  found  to  have  an  unusually  high 
percentage  of  salts.  If  a  moderate  quantity  of  a  dilute  solution  be  given, 
only  one  evacuation  follows,  but  large  doses  of  concentrated  solutions 
induce  repeated  stools,  which  at  first  contain  some  faecal  matter,  but 
later  consist  mainly  of  bile-stained  mucous  fluid. 

Action:  Intestine. — ^Tlie  saline  cathartics  differ  from  the  vegetable 
purgatives  in  not  inducing  irritation  of  the  intestine,  unless  when  they 
are  given  in  very  large  quantities.  The  characteristic  effect  is  not 
irritation,  but  retarded  absorption.  The  slow  absorption  of  the  salt 
entails  the  slow  absorption  of  the  fluid  in  which  it  is  dissolved,  for  the 
salt  holds  on  to  the  water  and  only  permits  of  its  being  taken  up  by 
the  bowel  if  an  equivalent  amount  of  salt  is  also  absorbed.  If  a  solution 
of  sodium  chloride  isotonic  with  the  blood  serum  be  administered  by 
the  mouth  to  a  dog  with  a  ca?cal  fistula,  little  or  none  of  it  reaches  the 
wound,  as  it  is  all  absorbed  in  the  stomach  and  small  intestine.  If, 
on  the  other  hand,  an  equal  amount  of  an  isotonic  solution  of  sodium 
sulphate  be  administered  in  the  same  way,  most  of  the  solution 
escapes  by  the  fistula,  only  some  10-20  per  cent,  having  been  absorbed 
by  the  stomach  and  small  intestine.  In  a  normal  dog  or  in  the  human 
subject,  a  much  larger  amount  of  fluid  therefore  reaches  the  large  intes- 
tine if  sodium  sulphate  be  dissolved  in  it  than  if  sodium  chloride  be 
used  instead.  The  contents  of  the  large  intestine  are  consequently 
more  fluid  than  usual,  and  are  passed  down  more  easily  toward  the 
rectum.  At  the  same  time  the  weight  and  distention  of  the  bowel 
induces  increased  peristalsis  and  the  whole  is  evacuated.  This  increased 
peristalsis  is  due,  however,  not  to  any  irritant  action  such  as  has  been 
found  to  be  induced  by  rhubarb  or  croton  oil,  but  to  the  large  amount 
of  fluid  contents. 

This  accelerated  passage  along  the  bowel  has  been  observed  in  man 
by  means  of  the  Rontgen  rays,  and  appears  to  resemble  that  previously 
described  in  animals.  When  the  distended  small  intestine  empties 
its  contents  into  the  colon,  the  large  bowel  adopts  a  more  rapid  but 
otherwise  normal  movement  and  this  leads  to  the  evacuation  of  the 
rectum;  the  flrst  stool  may  thus  be  of  almost  normal  consistency, 
but  this  is  generally  followed  by  a  profuse  watery  movement  which 
may  contain  the  greater  part  of  the  salt  administered. 

If  a  weaker  solution  of   sodium  sulphate  is  administered,  the  only 


SALINE  CATHARTICS  103 

(liflFerence  is  that  more  of  the  fluid  is  absorbed  and  less  readies  the 
large  intestine;  but  however  weak  the  sohition,  more  of  it  reaches 
the  laroe  intestine  than  if  a  correspondingly  weak  solution  of  common 
salt  had  been  given. 

If  a  hypertonic  solution  be  administered,  the  effect  is  somewhat 
difi^erent.  The  salt  is  still  unabsorbed,  but  it  draws  fluid  from  the 
blood  into  the  bowel  from  its  having  higher  osmotic  pressure  than  the 
blood.  A  similar  draining  of  the  body  fluids  occurs  when  concen- 
trated solutions  of  common  salt  reach  the  bowel,  but  the  cathartic 
salts  are  much  more  powerful,  because  they  do  not  pass  out  of  the 
bowel  into  the  blood  so  easily.  Instead  of  an  exchange  of  salt  and 
fluid  being  carried  on  by  the  blood  and  intestinal  contents,  the  blood 
gives  up  its  fluid  without  any  sufficient  compensation  in  salt.  Even- 
tually the  intestinal  fluid  becomes  isotonic,  and  then  some  absorption 
of  both  salt  and  fluid  occurs;  in  fact,  some  salt  has  been  absorbed  all 
along,  as  the  epithelium  is  not  absolutely  impermeable  to  the  cathartics. 
But  much  less  of  the  sulphate  is  absorbed  than  of  the  chloride  given 
in  equal  concentration,  and  as  a  general  rule  a  strong  solution  causes 
such  an  accumulation  of  fluid  that  the  bowel  becomes  distended  and 
evacuates  its  contents.  If,  however,  from  any  cause  this  fails  to  occur, 
a  gradual  absorption  follows  and  the  whole  salt  and  fluid  in  the  bowel 
is  absorbed.  These  salts  may  fail  to  purge,  for  example,  when  the 
blood  and  tissues  contain  very  little  fluid,  as  in  animals  which  have 
been  deprived  of  water  for  several  days  previously.  In  this  case  the 
osmotic  pressure  in  the  bowel  is  unable  to  draw  fluid  from  the  con- 
centrated blood,  which  on  the  other  hand  has  a  higher  attraction 
for  the  fluid  in  the  bowel  than  usual.  But  where  large  quantities  of 
fluid  are  present  in  the  tissues,  as  in  oedema  and  dropsy,  the  saline 
cathartics  drain  them  through  the  blood  into  the  bowel,  and  very 
profuse  evacuation  occurs,  with  the  disappearance  of  the  exudate. 

The  saline  cathartics  fail  to  penetrate  the  intestinal  epithelium, 
just  as  sodium  chloride  fails  to  penetrate  the  blood  corpuscles  (p.  26), 
through  some  peculiar  physical  character,  which  prevents  them  following 
the  ordinary  process  of  diffusion  and  which  is  at  present  unknown; 
In  this  relation  it  has  been  found  by  Hofmeister  and  Pauli  that  the 
purgative  salts  have  a  greater  tendency  to  precipitate  proteins  and 
have  less  tendency  to  permeate  into  unorganized  colloids  than  most  of 
the  non-purgative  salts.  In  numerous  other  instances  the  sulphates, 
tartrates,  and  other  cathartic  anions  have  proved  slower  in  permeating 
into  living  cells  than  the  chlorides  and  bromides,  and  their  eft'ects  on 
the  blood  cells,  muscle,  nerve,  and  some  other  tissues  show  marked 
deviations  from  those  of  the  halogen  salts.  Another  curious  relation 
between  the  purgative  anions  is  that  their  calcium  salts  are  all  very 
much  less  soluble  than  those  of  the  salts  which  penetrate  the  epithelium, 
and  it  seems  probable  that  they  precipitate  the  calcium  in  the  bowel 
wall.  Most  of  the  cathartic  anions  are  bivalent  or  trivalent,  but  this 
is  not  true  for  all  of  them,  for  the  higher  members  of  the  acetate  series 
are  absorbed  with  the  greatest  difficulty  by  the  intestine. 


104  SUBSTANCES  ACTING  LOCALLY 

The  saline  cathartics  induce  certain  changes  in  the  Blood  indirectly 
thron^h  their  action  on  the  intestine.  They  prevent  the  absorption 
of  the  finid  of  the  food,  or,  if  in  snfficient  concentration,  actually  draw 
fluid  from  the  blood  and  tissues  into  the  bowel,  and  under  both  con- 
ditions the  blood  becomes  more  concentrated  than  usual;  in  the  first 
case  because  it  is  not  reinforced  by  the  usual  amount  of  fluid  from 
the  food,  in  the  second  because  it  actually  loses  fluid  into  the  intestine. 
This  concentration  of  the  blood  leads  to  a  sensation  of  thirst,  and  to 
a  lessened  excretion  of  fluid  by  the  kidneys  and  other  glands. 

A  certain  amount  of  salt  and  of  fluid  is  absorbed  from  the  intestine, 
unless  purgation  follows  very  rapidly,  and  this  salt  acts  in  the  blood 
and  tissues  in  the  same  way  as  the  salts  which  do  not  act  as  cathartics. 
When  very  dilute  solutions  of  these  salts  are  given,  therefore,  the 
blood  becomes  less  concentrated  and  diuresis  follows,  but  this  does 
not  occur  so  soon  as  after  a  similar  solution  of  common  salt,  because 
the  absorption  is  somewhat  slower.  Stronger  cathartic  solutions 
at  first  cause  a  concentration  of  the  blood  and  lessened  urine,  but 
afterward  the  excess  of  salt  in  the  blood  may  cause  diuresis.  The 
greater  the  purgative  action,  the  less  the  diuretic,  because  more  fluid 
and  more  of  the  cathartics  are  thrown  out  in  the  stools.  If  no  purga- 
tion follows  for  any  reason,  as  when  the  blood  has  been  concentrated 
by  long  abstinence  from  water,  the  whole  of  the  salt  eventually  passes 
into  the  blood  and  is  excreted  by  the  kidney,  and  may  cause  very  con- 
siderable diuresis  and  a  still  further  concentration  of  the  blood.  The 
sulphates  are  absorbed  by  the  epithelium  of  the  renal  tubules  with 
mych  greater  diflSculty  than  chloride,  and  thus  offer  osmotic  resistance 
to  the  absorption  of  the  fluid  in  the  tubules;  sulphates  absorbed  into 
the  blood  therefore  induce  a  more  profuse  diuresis  than  an  equal  amount 
of  chloride,  but  less  of  the  former  reaches  the  blood  generally,  so  that 
the  chlorides  are  better  practical  diuretics. 

From  the  above  it  can  be  at  once  inferred  that  a  saline  cathartic 
injected  intravenously  causes  no  purgation,  for  instead  of  preventing 
the  passage  of  fluid  from  the  bow^el  into  the  blood,  it  rather  encourages 
its  absorption  l)y  increasing  the  osmotic  pressure  of  the  blood.  And 
similarly  the  hypodermic  injection  of  these  salts  is  not  followed  by 
purging.  A  certain  amount  of  discussion  has  been  carried  on  in  the 
last  few  years  on  this  point,  but  the  result  has  been  to  confirm  this 
view  and  to  indicate  that  experiments  w^hich  seemed  to  oppose  it  were 
erroneously  performed. 

The  statement  is  sometimes  made  that  the  saliiu>  cathartics  act  as 
cholagogues,  i.  e.,  increase  the  secretion  of  bile,  l)iit  this  has  not  been 
coiiflmicd  l)y  more  careful  observations. 

The  Temperature  is  often  somewhat  reduced  by  the  action  of  the 
saline  cathartics,  but  seldom  more  than  one-half  degree. 

The  habitual  use  of  saline  cathartics  is  often  eflicient  in  Reducing 
the  Weight  in  obcsitN',  and  many  of  the  natural  mineral  waters  have 
a  considcraidc  reputation  in  the  treatment  of  such  cases.  This  appears 
to  be  due  ill  part  to  less  proteins  and  fats  being  absorbed  from  the 


SALINE  CATHARTICS  105 

intestine,  in  part  to  the  fluids  of  the  ])ody  being  decreased.  There 
seems  no  reason  to  suppose  that  any  marked  chanfjje  in  the  nitrogenous 
metabolism  is  induced  by  the  cathartics,  for  the  nitrogen  in  the  urine 
is  often  practically  unaltered  in  amount. 

When  purgation  follows  the  administration  of  a  saline  cathartic, 
the  most  of  the  salt  escapes  in  the  fteces,  never  having  been  absorbed 
at  all.  When  the  salt  fails  to  purge,  however,  and  is  absorbed,  it 
undergoes  the  usual  exchanges  in  the  tissues  and  is  excreted  by  the 
urine.  There  is  no  reason  to  suppose  that  any  of  it  appears  again  in 
the  stomach  or  intestine. 

The  Sulphates  seem  to  pass  through  the  tissues  without  injuring  them, 
and  but  little  effect  is  observed  from  injecting  considerable  quantities  into 
the  blood.  When  the  sulphate  ion  is  combined  with  a  poisonous  base,  such  as 
potassium  or  magnesium,  the  injection  is  of  course  followed  by  characteristic 
symptoms;  but  the  anion  seems  to  be  comparatively  harmless,  and  when  the 
potassium  or  magnesium  salt  is  taken  by  the  mouth  it  also  is  quite  devoid  of 
general  action. 

The  Phosphates  are  also  very  mactive  after  absorption.  When  they  are 
injected  subcutaneously  or  intravenousl}^  the  metaphosphates  and  pyrophos- 
phates are  poisonous,  but  this  appears  to  be  due  to  their  alkalinity  (Starken- 
stein).  Phosphates  absorbed  in  man  and  in  the  carnivora  are  excreted  by  the 
kidnej'  and  increase  the  acidity  of  the  urine;  in  the  herbivora  they  are  excreted 
exclusively  by  the  bowel  wall. 

The  Tartrates  are  slowly  oxidized  in  the  tissues  to  carbonates  but  a  con- 
siderable quantity  is  excreted  in  the  urine  unchanged.  Injected  into  the  blood 
direetlj^,  the  tartrates  seem  to  act  as  heart  poisons,  and  in  the  rabbit  nephritis 
is  induced  by  their  hypodermic  application,  but  no  such  effects  are  observed 
in  man  from  their  administration  by  the  mouth  even  in  enormous  quantities. 

The  oxide  and  carbonate  of  magnesium  differ  from  the  other  saline 
cathartics  in  being  very  insoluble  and  in  possessing  an  alkaline  reaction. 
Part  of  that  ingested  is  formed  into  magnesium  chloride  in  the  stomach, 
however,  and  the  carbonic  acid  present  in  the  intestine  may  dissolve 
part  by  forming  the  bicarbonate.  Their  alkalinity  serves  to  remedy 
any  excessive  acidity  of  the  stomach  or  intestine,  while  at  the  same 
time  they  are  mildly  cathartic.  The  prolonged  use  of  large  quantities 
of  magnesia  has  in  some  cases  led  to  the  formation  of  large  concretions 
in  the  bowel,  resulting  in  obstruction. 


Preparations. 

SoDii  Sulphas  (U.  S.  P.,  B.  P.),  Glauber's  salt  (Na.>S04,  lOITO),  soluble  in 
about  3  parts  of  cold  water,  16  G.  (240  grs.);  B.  P.,  30-240  grs. 

Magnesii  Sulphas  (U.  S.  P.,  B.  P.),  Epsom  salts  (MgSO^,  7H.0),  soluble  in 
U  parts  of  cold  water,  16  G.  (240  grs.);  B.  P.,  30-240  grs. 

These  are  crystalline  salts  with  a  harsh,  bitter  taste. 

SoDii  Phosphas  (U.  S.  p.,  B.  P.)  (Na2HP04  +  12H,0),  a  crystalline  salt 
with  a  cool,  saline  taste,  soluble  in  about  6  parts  of  cold  water,  2  G.  (30  grs.); 
B.  p.,  30-120  grs.  (repeated),  150-240  grs.  (single). 

Liquor  Sodii  Phosphatis  Compositus  (U.  S.  P.)  contains  sodium  nitrate  and 
citric  acid.    Dose,  8  c.c.  (2  fl.  drs.). 


106  SUBSTANCES  ACTING  LOCALLY 

Potassii  Bitartras  (U.  S.  P.),  Potassi  Tartras  Acidus  (B.  P.),  cream  of  tartar 
(KlIC4H40fi),  a  crystalline  powder  with  a  pleasant  acidulous  taste,  soluble  in 
200  parts  of  water,  2  G.  (30  grs.);   B.  P.,  15-60  grs. 

Potassii  et  8odii  Tautuas  (U.  S.  P.,  B.  P.),  Rochelle  salt  (KNaC4H406 
+  4H2O),  crystals  or  powder  with  a  cool  saline  taste,  soluble  in  1.2  parts  of 
cold  water,  8  Ci.  (120  grs.);  B.  P.,  120-240  grs. 

Magnesia  (B.  P.),  Magnesii  Oxidum  (U.  S.  P.),  magnesia  (MgO).  2  G. 
(30  grs.);   B.  P.,  5-60  grs. 

Magnesii  Caubonas  (U.  S.  P.,  B.  P.)  (MgC03)4Mg(OH)2  +  SH^O).  3  G. 
(45  grs.);    B.  P.,  5-60  grs. 

These  form  white  amorphous  powders  with  an  earthy,  not  saline,  taste. 
They  are  insoluble  in  water,  but  the  carbonate  is  dissolved  by  excess  of  carbonic 
acid. 

EfEervescing  Preparations. 

PuLVis  Effervescens  Compositus  (U.  S.  p.),  PuLVis  SoD^  Tartarat.e 
Kffervescens  (B.  P.),  Seidlitz  powder. 

This  powder  is  made  up  in  two  papers,  of  which  the  blue  one  contains  a 
mixture  of  3  parts  of  Rochelle  salts  and  one  part  of  sodium  bicarbonate,  in  all 
10.4  G.  (160  grs.),  while  the  white  paper  contains  2.25  G.  (2.5  G.  B.  P.)  of 
tartaric  acid.  When  the  powders  are  dissolved  separately  in  water  and  the 
solutions  mixed,  the  tartaric  acid  acting  on  the  bicarbonate  releases  carbonic 
acid  with  effervescence. 

Liquor  Magnesii  Citratis  (U.  S.  P.)  is  a  solution  of  magnesium  citrate  with 
excess  of  citric  acid  to  w^hich  potassium  bicarbonate  is  added.  The  w^hole  is 
bottled  tightly  and  effervesces  when  the  cork  is  removed.    360  c.c.  (12fl.  oz.). 

Magnesii  Sulphas  Effervescens  (B.  P.,  U.  S.  P.),  a  mixture  of  Epsom  salts, 
sodium  bicarbonate,  tartaric,  and  citric  acids,  which  effervesces  when  mixed 
with  water.  16  G.  (240  grs.);  B.  P.,  60-180  grs.  for  repeated  administration; 
for  a  single  administration  |-1  oz. 

Sodii  Sulphas  Effervescens  (B.  P.),  a  similar  mixture  containing  the  sulphate 
of  soda  instead  of  that  of  magnesia.  60-120  grs.  for  repeated  administration; 
for  a  single  administration  j-|  oz. 

Sodii  Fhosphas  Effervescens  (B.  P.,  U.  S.  P.),  similar  to  the  above,  but  con- 
taining the  phosphate  in  place  of  the  sulphate.  8  G.  (120  grs.);  B.  P.,  60-120 
grs.  for  repeated  administration  and  \-\  oz.  for  a  single  administration. 

Many  other  effervescent  mixtures  are  used  instead  of  the  official  ones— among 
them  the  tartrates  and  citrates  of  the  alkalies,  the  acetate  of  magnesium,  etc. 

The  sulphates  of  sodium  and  of  magnesium,  the  tartrates  of  sodium  and 
potassium  and  the  phosphate  of  sodium  are  given  in  solution,  the  last  often  in 
milk.  Unless  under  special  conditions  the  salts  ought  not  to  be  in  greater 
concentration  than  5-10  per  cent.  Magnesia  and  magnesium  carbonate  are 
administered  in  powder,  sweetened  if  necessary.  The  effervescent  preparations 
arc  always  to  be  taken  in  solution  in  about  a  tumbler  of  water;  in  some  instances 
in  which  this  was  not  understood,  severe  distention  of  the  stomach  with  alarm- 
ing symptoms  have  arisen  from  the  carbonic  acid  being  freed  in  the  stomacli. 
The  effervescent  preparations  ought  to  be  kept  dry,  and  the  solution  t)f  mag- 
nesium citrate  has  to  be  kei)t  tightly  corked. 

Very  often  the  natural  mineral  waters  are  used  instead  of  the  pharmaco- 
poeial  preparations,  the  best  known  purgatives  among  tliesc  being  the  Ilunyadi- 
Janos  water  and  Carlsbad  water,  which  contain  the  sulphates  of  sodium  and 
magnesium.  "Carlsbad  salts"  are  obtained  by  the  evaporation  of  the  waters, 
but  are  very  often  artificial  imitations.  Many  other  springs  have^  the  same 
effects,  and  a  widespread  belief  exists  that  the  natural  waters  are  "more  effi- 
cient" or  "less  depressant"  or  have  some  mystical  virtues  that  are  not  shared 
in  by  the  artificial  salts,  but  this  belief  docs  not  seem  to  liave  any  real  basis, 
and  is  probably  a  survival  of  ttie  old  religious  belief  in  the  healing  properties 
of  springs. 


SALINE  CATHARTICS  107 

In  the  natural  waters  the  purgative  salts  are  always  accompanied  [ly  othci' 
less  active  ones,  such  as  the  chlorides  of  sodium,  calcium,  etc. 

Agar-Agar  may  be  mentioned  here  as,  although  it  has  no  chemical  relation  to 
the  saline  cathartics,  its  action  presents  certain  analogies  and  it  has  been  used 
for  similar  puiposes.  It  is  obtained  from  various  East  Indian  sea-weeds,  and 
consists  mainly  of  gelose,  a  carbohydrate  which  is  indigestible  and  unabsorl)able 
and  retains  water  in  the  alimentary  canal  in  the  same  way  as  the  saline  cathar- 
tics. It  thus  increases  the  bulk  of  the  contents  of  the  bowels  and  causes  their 
evacuation.  It  is  used  in  constipation  in  quantities  of  5-15  G.  (75-225  grs.), 
either  suspended  in  water  or  food.    It  is  almost  tasteless. 

Other  inert  and  unabsorbable  fluids  may  be  used  to  increase  the  intestinal 
contents  and  thus  promote  peristalsis;  thus  the  liquid  petrolate  or  paraffin 
(p.  48)  has  been  advised  in  constipation. 

Therapeutic  Uses. — The  saline  cathartics  are  very  largely  used  to 
relieve  constipation.  Habitual  constipation  seems  to  be  caused  by 
insufficient  peristalsis,  and  the  slow  passage  of  the  contents  through 
the  intestines  allows  of  a  more  complete  absorption  than  usual,  this  in 
turn  rendering  the  fseces  hard  and  dry  and  difficult  to  move  onward. 
The  saline  cathartics  increase  the  fluidity  of  the  intestinal  contents, 
and  thus  facilitate  their  expulsion,  and  this  is  probably  the  only  effect 
they  have  when  taken  in  small  quantities,  and  especially  in  dilute 
solution  as  in  the  natural  mineral  waters.  In  larger  quantities,  how- 
ever, more  water  is  retained  in  the  bow^el,  and  the  weight  and  disten- 
tion cause  peristalsis,  while  in  sufficient  quantity  they  draw  fluid 
from  the  blood  and  cause  profuse  watery  discharges.  When  a  very 
complete  evacuation  is  desired,  the  saline  cathartics  may  be  given 
along  with  some  of  the  vegetable  purgatives.  Such  mixtures  are  the 
official  Black  Draught  (see  Senna)  and  the  compound  powder  of  Jalap. 
The  saline  cathartics  act  much  more  rapidly  than  the  vegetable  pur- 
gatives, and  a  common  method  of  combining  their  efi^ects  is  to  give 
the  latter  in  the  evening  and  the  saline  the  following  morning;  in  the 
same  way  a  mercurial  purge,  such  as  calomel,  given  in  the  evening, 
may  be  followed  by  a  Seidlitz  powder  in  the  morning. 

The  chronic  constipation  due  to  sedentary  habits  is  much  benefited 
by  the  saline  cathartics,  more  especially  l)y  dilute  solutions  taken 
before  breakfast.  The  sulphates  and  tartrates  are  harsh  and  unpleasant 
to  the  taste,  and  the  natural  waters  are  often  preferred,  or  one  of 
the  effervescent  preparations  may  be  used  in  those  cases. 

The  sulphates  and  tartrates  are  more  frequently  used  where  a  single 
large  dose  has  to  be  prescribed  in  order  to  empty  the  bowel,  but  here 
also  the  Seidlitz  powder  may  be  advised  instead,  as  being  more  agreeable 
to  the  taste.  These  cathartics  were  at  one  time  used  in  fever,  partly 
from  a  theory  that  they  reduced  the  temperature;  they  are  certainly 
less  liable  to  cause  pain  and  griping  than  the  vegetable  purgatives, 
and  thus  tend  to  disturb  the  patient  less. 

The  sodium  phosphate  is  often  prescribed  for  children,  either  as  a 
powder  to  be  given  in  jelly,  or  in  solution  in  milk  or  other  food,  which 
completely  hides  its  taste. 

The  saline  cathartics  are  used  to  lessen  intestinal  putrefaction,  and 


I 


108  SUBSTANCES  ACTING  LOCALLY 

are  sometimes  very  efficient,  though  tliey  do  not  act  through  any  anti- 
septic power,  but  simply  by  remoxing  the  putrefying  mass.  The 
phosphate  of  sodium  has  l)ecn  especially  recommended  in  some  forms  of 
diarrha?a  in  children. 

The  saline  cathartics  are  administered  to  remove  accumulations  of 
fluid  in  the  body  arising  from  cardiac  or  renal  insufficiency,  or  from 
an  old  effusion.  For  this  purpose  the  sulphate  of  magnesium  is  used 
in  a  large  dose,  dissolved  in  about  its  own  weight  of  water;  if  purgation 
does  not  follow  in  1-3  hours,  an  enema  may  be  necessary,  or  the  saline 
may  be  given  along  with  a  vegetable  purgative.  This  form  of  treat- 
ment was  very  popular  at  one  time,  but  is  liable  to  weaken  and  depress 
the  patient,  and  is  specially  contra-indicated,  therefore,  in  asthenic 
conditions.  Other  methods  of  removing  accumulations  of  fluid  are  by 
the  use  of  diuretics  (see  caffeine),  diaphoretics  (see  pilocarpine),  or 
cardiac  remedies  (digitalis). 

As  diuretics  the  saline  cathartics  are  inferior  to  other  salts,  such 
as  the  acetates  or  nitrates.  Large  quantities  of  dilute  solutions  of  the 
purgative  salts  are  of  value  in  the  treatment  of  some  forms  of  obesity, 
the  mineral  waters  being  generally  prescribed  for  this  purpose,  or  the 
patient  being  sent  to  drink  them  at  their  source. 

Magnesia  and  magnesium  carbonate  are  less  liable  to  purge  than 
the  soluble  salts,  and  are  specially  indicated  in  hyperacidity  of  the 
stomach  or  in  acid  putrefaction  in  the  bowel.  They  cause  less  irritation 
than  the  carbonates  of  the  alkalies  because  of  their  insolubility,  and 
at  the  same  time  have  the  advantage  of  acting  as  mild  purgatives, 
while  the  lime  preparations  which  are  insoluble,  tend  to  induce  con- 
stipation. The  magnesia  preparations  may  be  used  also  in  diarrhoea 
as  antacids,  as  they  have  no  irritant  action  on  the  bowel.  A  com- 
bination of  antacid,  carminative,  saline  and  vegetable  aperient  is  found 
in  Gregory's  powder,  which  contains  magnesia,  rhubarb,  and  ginger 
(p.  94).  Freshly  prepared  magnesia  is  recommended  in  arsenic  poison- 
ing to  form  an  insoluble  precipitate  in  the  stomach,  and  in  poisoning 
with  acids  it  is  also  of  value  when  it  can  be  obtained  readily.  In  both 
cases  it  is  to  be  given  in  large  quantities. 

The  phosphate  of  sodium  has  been  given  in  various  bone  diseases,  as  in  osteo- 
malacia and  rickets,  this  treatment  being  founded  on  the  belief  that  the  soften- 
ing of  the  bones  is  due  to  the  lack  of  phosphates  in  the  food,  but  there  is  no 
reason  to  suppose  that  this  idea  is  correct,  and  the  treatment  is  not  attended 
witli  success.  It  has  also  been  reconnnended  in  the  uric  acid  diathesis.  The 
phospliatcs  have  been  supposed  to  be  of  benefit  in  nervous  diseases,  on  the 
theory  tliat  these  were  due  to  the  insufficiency  of  phosphorus  in  the  brain,  and 
glycero-phosphates  have  been  introduced  for  the  same  reason,  but  there  is 
never  anj'  deficiency  in  the  supply  of  phosphates  in  the  footl,  and  in  practice 
no  benefit  is  seen  from  the  use  of  these  salts. 

Bibliography. 

Hay.  Saline  cathartics,  Journ.  of  Anat.  and  Phys.,  xvi  and  xvii;  also  in  monograph, 
Kdinhurgh,   1884. 

London.     Zts.  f.  klin.   Mod.,  xiii,  p.  48. 

Dapper.    Ibid.,  xxx,  p.  371.    Arcli.  f.  Verdauungskrank,  ill,  p.  1. 


VEGETABLE  ASTRINGENTS  ]()() 

Heidenhain.     Pfluger's  Archiv,   Ivi,   p.   579. 

Kovesi.    Ccntralbl.  f.  Physiol.,  1897,  p.  553. 

Hamburger.     Arch.  f.  Anat.  u.  Phys.,  1896,  p.  428. 

Hober.     Pfliiger's  Archiv,  Ixx,  p.  624. 

Wallace  and  Cushny.    Am.  Journ.  of  Physiol.,  i,  p.  411.    Pfliiger's  Archiv,  Ixxvii,  p.  202. 

Gamgee,  Priestley,  and  Larmuih.    Journ.  of  Anat.  and  Phys.,  xi,  p.  255.     (Phosphates.) 

Bergmann.    Arch.  f.  exp.  Path.  u.  Pharm.,  xlvii,  p.  77. 

Swiatecki.    Ztschr.  f.  phys.  Chem.,  xv,  p.  49. 

Padtberg.     Arch.  f.  d.  ges.  Physiol.,  cxxix,  p.  476. 

Heer.     Arch,  internat.  de  Pharmacodyn.,  xxi,  p.  321. 


X.    VEGETABLE  ASTRINGENTS     TANNIC  ACID  SERIES. 

A  large  number  of  vegetable  substances  owe  their  action  to  their 
containing  tannin  substances,  while  in  many  other  preparations  the 
effect  of  more  important  constituents  is  modified  by  the  presence  of 
these  widely  distributed  bodies.  Tannic  acid  proper  (C14H10O9)  is 
a  very  feebly  acid  substance  derived  from  the  oak  gall,  and  seems  to 
consist  of  an  anhydride  combination  of  gallic  acid,  CvHeOs,  into  which 
it  is  very  easily  decomposed.  Gallic  acid  is  formed  from  a  large  number 
of  other  bodies  which  closely  resemble  tannic  acid  in  their  general 
features,  but  are  by  no  means  identical  with  it.  Their  constitution 
is  altogether  unknown,  but  they  possess  a  number  of  reactions  in 
common  and  are  generally  classed  together  as  the  tannic  acid  substances. 
Some  of  them  contain  a  sugar,  and  tannin  or  tannic  acid  is  therefore 
sometimes  said  to  be  a  glucoside.  These  bodies  precipitate  albumins, 
gelatin,  alkaloids  and  some  glucosides,  and  the  salts  of  the  heavy 
metals;  the  salts  of  iron  form  a  bluish-black  or  greenish-black  precipi- 
tate. 

Action. — The  pharmacological  effects  of  these  bodies  are  due  to 
their  precipitating  albumins  and  other  proteins,  and  this  reaction 
may  therefore  be  described  before  their  action  in  the  body.  If  tannic 
acid  solution  be  added  to  a  neutral  solution  of  albumin  or  gelatin, 
a  white  precipitate  falls,  which  is  entirely  insoluble  in  water,  but  is 
soluble  in  excess  of  albumin  or  gelatin,  in  acetic  or  lactic  acid,  and  in 
alkaline  solutions.^  Solutions  of  pepsin  and  of  peptones  are  also  pre- 
cipitated by  tannic  acid  unless  in  the  presence  of  an  acid.  If  protein 
tannate  be  exposed  to  the  action  of  the  gastric  juice,  it  undergoes 
digestion  and  is  dissolved  in  the  same  way  as  an  ordinary  coagulated 
protein  such  as  fibrin.  During  the  process  the  tannic  acid  is  set  free 
from  its  combination  apparently,  and  can  precipitate  undigested 
proteins,  although  it  has  no  effect  on  the  peptones  in  the  acid  medium. 
When  a  soluble  tannate  is  formed  by  the  addition  of  soda  or  potash  to 
a  tannic  acid  solution,  the  presence  of  proteins  produces  no  precipitate, 
the  affinities  of  the  acid  being  satisfied  by  the  alkali,  and  for  the  same 
reason  the  tannic  acid  precijMtate  is  dissolved  in  the  presence  of  alkalies. 

Tannic  acid  applied  to  animal  tissue,  as  in  the  tanning  of  leather, 
causes  a  precipitation  of  the  proteins,  and  the  tissue  becomes  harder 

'  Some  discrepancies  in  the  accounts  of  different  authors  in  regard  to  these  reactions 
are  perhaps  due  to  variations  in  the  amount  of  the  neutral  salts  in  their  preparations. 


110  SUBSTANCES  ACTING  LOCALLY 

and  tougher  and  tends  to  shrink  together;  at  the  same  time  it  has  less 
tendency  to  undergo  putrefactive  changes  and  does  not  lose  its  flexi- 
biUty,  as  it  would  in  drying. 

Tannic  acid  solutions  have  a  harsh,  bitter,  "astringent"  taste,  and 
produce  in  the  mouth  a  feehng  of  constriction,  dryness  and  roughness, 
along  with  a  sense  of  stiffness  in  the  movements  of  the  tongue,  and  some 
loss  of  taste.  These  effects  are  due  to  the  coagulation  of  the  superficial 
layers  of  protein  both  within  and  without  the  epithelium,  which  substi- 
tutes for  the  ordinary  smooth  surface  a  firmer,  less  even  one  over  which 
the  tongue  can  no  longer  move  easily.  The  feeling  of  constriction  may, 
perhaps,  be  caused  by  an  actual  shrinking  of  the  superficial  layers  of 
the  epithelium,  or  may  be  due  merely  to  the  impaired  movements  and 
sensation. 

The  astringent  'feeling  is  continued  in  the  throat  as  the  solution  is 
swallowed,  and  occasionally  some  discomfort  or  even  nausea  and  vomit- 
ing are  provoked  by  it,  but  as  a  general  rule,  no  such  effects  are 
observed.-  The  stools  are  rendered  harder  and  firmer  by  the  admin- 
istration of  tannic  acid,  and  constipation  is  often  produced  by  it.  In 
excess,  tannic  acid  sometimes  causes  irritation  of  the  intestine  and 
diarrhoea,  but  beyond  these  s\Tiiptoms  of  local  irritation  of  the  stomach 
and  bowel,  no  effects  arise  from  even  enormous  quantities  of  the  drug. 

In  the  stomach,  tannic  acid  combines  with  any  protein  substance 
with  which  it  may  come  in  contact  and  precipitates  it,  but  as  digestion 
progresses,  this  combination  is  broken  up,  as  the  peptones  do  not  com- 
bine with  tannic  acid  in  acid  solution,  and  the  astringent  action  is 
therefore  exercised  on  the  walls  of  the  stomach  and  intestine.  Ordinary 
quantities  cause  the  same  superficial  coagulation  as  in  the  mouth, 
but  if  large  doses  be  given  when  the  stomach  and  intestine  are  not 
protected  by  foodstuffs,  a  more  complete  coagulation  of  the  mucous 
membrane  takes  place  and  the  consequent  irritation  results  in  vomit- 
ing, and  sometimes  in  diarrhoea.  The  increase  in  the  consistency  of 
the  stools  is  probably  due  to  the  layer  of  coagulated  protein  acting  as 
a  protective  to  the  bowel,  lessening  its  irritability  and  thus  retarding 
its  movements  so  that  there  is  longer  time  for  the  absorption  of  the 
fluid  part  of  its  contents,  although  this  proceeds  more  slowly  imder 
tannic  acid  than  normally  (Gebhardt).  The  secretion  of  nnicus  by 
the  intestinal  epithelium  is  lessened  (Frey),  and  this  may  also  retard 
the  passage  of  the  contents.  Hesse  states  that  the  constipating  action 
is  exercised  chiefly  in  the  large  bowel  when  tannalbin  is  given,  but  this 
may  not  hold  for  the  ordinary  forms  of  taimin.  Yeasts  and  microbes 
are  ])recipitat('d  by  tannin,  and  this  may  tend  to  lessen  the  fermenta- 
tion in  the  bowel  in  some  cases,  although  some  prei)arati()ns  of  tannic 
acid  which  have  been  examined  in  regard  to  this  pt)int  have  ])vvu  found 
t(t  ha\('  little  or  no  effect  on  intestinal  ])utrefaction. 

Tlir  lo(;il  ;i|»|)licatioii  of  taiiiiic  acid  causes  a  (liniiiiutioii  of  the 
secretions  of  glands,  as  has  been  demonstrated  by  Sehiit/,.  This  is 
due  to  its  effects  upon  the  ])rotoplasm  of  the  secreting  cells,  which 
probably  undergo  the  initial  stages  of  coagulation. 


VEGETABLE  ASTRINGENTS  111 

It  is  often  stated  that  tannic  acid  constricts  the  vessels  of  any  part 
to  which  it  is  applied,  but  this  is  not  supported  by  accurate  observations. 
In  acting  as  a  protective  to  mucous  surfaces,  it  may  reduce  congestion, 
but  there  is  no  reason  to  suppose  that  it  acts  more  directly  on  the  vessel 
walls,  or,  in  fact,  that  it  ever  reaches  them  in  an  active  form.  In  the 
same  way  it  may  indirectly  lessen  the  inflammatory  exudation  from 
the  vessels  and  the  leucocytosis. 

When  tannic  acid  comes  in  contact  with  blood  in  a  test-tube  it  pre- 
cipitates the  proteins,  and  when  it  is  injected  intravenously^  the  pre- 
cipitate formed  leads  to  the  formation  of  emboli. 

The  fate  of  tannic  acid  in  the  body  has  given  rise  to  some  discussion. 
When  it  is  taken  internally,  a  small  proportion  is  sometimes  eliminated 
by  the  bowel  unchanged,  but  very  often  none  is  to  be  found  in  the  stools; 
traces  are  apparently  absorbed  and  excreted  in  the  urine  in  both  man 
and  animals,  although  some  investigators  have  failed  to  detect  these. 
When  sodium  tannate  is  administered  internally,  a  distinctly  larger 
amount  of  it  is  absorbed  and  reappears  in  the  urine.  But  much  the 
greater  part  of  the  tannic  acid  is  decomposed  in  the  intestine  into  gallic 
acid,  some  of  which  often  passes  out  in  the  stools,  some  in  the  urine. 
Only  about  1  per  cent,  of  the  tannic  acid  swallowed  reappears  in  the 
excretions,  either  as  tannic  or  gallic  acid;  the  rest  apparently  undergoes 
complete  oxidation  in  the  tissues,  for  no  further  trace  of  it  can  be  found. 
After  tannic  acid  is  administered,  some  tannic  or  gallic  salt  is  present 
in  the  blood,  for  iron  salts  give  a  darker  color  to  it,  but  it  is  impossible 
to  state  whether  this  is  tannin  or  a  gallate,  although  in  all  probabiUty 
it  is  the  latter.  According  to  Harnack,  the  gallic  acid  in  the  urine 
sometimes  forms  pyrogallol  on  standing,  but  this  poisonous  substance 
is  not  formed  from  tannic  acid  in  the  intestine  or  tissues. 

Tannic  acid  then  does  not  exist  in  the  tissues  as  such,  but  only  in 
the  form  of  traces  of  the  gallate  or  tannate  of  sodium,  which  are  so 
.small  as  to  be  devoid  of  astringent  properties.  The  effects  of  tannic 
acid  are  therefore  limited  to  the  point  of  application,  and  there  is  no 
evidence  of  any  weight  that  it  exercises  any  action  after  absorption. 
The  alkaline  tannates  are  generally  believed  to  be  entirely  devoid  of 
astringent  effects,  but  the  tannic  acid  is  freed  to  some  extent  by  such 
feeble  acids  as  carbonic  acid,  so  that  the  astringent  action  is  present 
in  the  intestine. 

Tannic  acid  is  often  said  to  lessen  the  albuminuria  in  certain  forms  of  Bright's 
disease,  but  the  only  exact  determinations  which  have  been  made  in  man 
showed  that  no  such  effect  was  present,  and  in  Ribberts'  experiments  the 
animals  were  moribund  when  the  improvement  occurred,  and  no  safe  deduc- 
tions can  be  made  therefore.  The  urine  is  sometimes  said  to  be  diminished 
JDy  tannic  acid,  but  this  statement  is  based  on  error.  Last  of  all,  tannic  acid 
IS  said  to  lessen  internal  ha^norrhage  by  contracting  the  vessels,  but  tannate 
of  soduim,  the  only  form  in  which  it  can  exist  in  the  blood  is  entirely  devoid  of 
action. 

Gallic  acid  given  by  the  mouth  is  aljsorbed  and  is  («xcreted  l)y  the  kidneys 
to  sonie  extent.  Much  of  it  disappears  in  the  tissues,  however,  apparently  by 
oxidation.  Gallic  acid  has  no  astringent  properties  and  is  quite  useless  in 
therapeutics. 


112  SUBSTANCES  ACTING  LOCALLY 

Tlio  numerous  preparations  of  the  pharmacoptcias  whieli  owe  their  activity 
to  their  containing  tannic  acid,  (Uffei-  from  the  pure  drug  in  that  the  acid  is 
only  slowly  dissolved  out  from  the  colloid  mass,  and  therefore  acts  less  on  the 
stomach  and  affects  a  greater  length  of  intestine. 

Preparations. 

Acidum  Taimicum  (U.  S.  P.,  B.  P.),  tannic;  acid,  gallotannic  acid  or  digallic 
acid  (HC14II9O9),  an  organic  acid  obtained  from  nut-gall.  0.5  G.  (7-2-  grs.); 
B.  P.,  5-10  grs. 

Glyceritum  Acidi  Tannici  (U.  S.  P.),  Glycerinum  Acidi  Tannici  (B.  P.). 

Unguentum  Acidi  Tannici  (U.  S.  P.),  20  per  cent. 

Trochisci  Acidi  Tannici  (U.  S.  P.),  0.06  G.  (1  gr.);   (B.  P.),  i  gr.  in  each. 

Suppositoria  Acidi  Tannici  (B.  P.),  0.2  G.  (3  grs.)  in  each. 

Gambir  (U.  S.  P.),  an  extract  prepared  from  the  wood  of  Ourouparia  Gambir, 
1  G.   (15  grs.). 

TiNCTURA  Gambir  Composita  (U.  S.  P.),  (flavored  with  cinnamon),  4  c.c. 
(1  fl.  dr.). 

Gambir  has  been  substituted  for  the  Catechu  of  former  editions  of  the  U.  S.  P. 

Catechu  (B.  P.),  an  extract  of  the  leaves  and  young  shoots  of  Uncaria 
Gambler,  5-15  grs. 

TiNCTURA  Catechu,  |-1  fl.  dr. 

Trochiscus  Catechu,  each  containing  0.06  G.  (1  gr.)  of  catechu. 

Pubis  Catechu  Cotnpositus  contains  catechu,  kino,  krameria,  cinnamon,  and 
nutmeg,  10-60  grs. 

Krameria  (U.  S.  P.),  Kramerise  Radix  (B.  P.),  Rhatany,  the  root  of  Krameria 
triandra,  Krameria  ixina  and  Krameria  argentea. 

ExTRACTUM  Krameria  (B.  P.),  0.3-1  G.  (5-15  grs.). 

Fhddextracium  Kramerice  (U.  S.  P.),  1  c.c.  (15  mins.). 

Tinctura  Krameria^  (U.  S.  P.,  B.  P.),  4  c.c.  (1  fl.  dr.);   B.  P.,  \-l  fl.  dr. 

Trochiscus  Kramerice  (B.  P.),  each  containing  1  gr. 

Kino  (U.  S.  P.,  B.  P.),  the  inspissated  juice  of  Pterocarpus  Marsupium,  0.5 
G.  (71  grs.);  B.  P.,  5-20  grs. 

TiNCTURA  Kino  (U.  S.  P.,  B.  P.),  4  c.c.  (1  fl.  dr.);  B.  P.,  i-1  fl.  dr. 

PuLVis  Kino  Compositus  (B.  P.),  contains  5  per  cent,  of  opium,  5-20  grs. 

Other  astringent  drugs  of  this  series,  which  offer  no  advantages  over  those 
already  given  are  AVitchhazel  (Hamamelidis  Folia  and  Cortex),  the  leaves 
and  bark  of  Hamamelis  Virginiana;  Logwood  {H(pmatoxyloti),  the  wood  of 
Ha^matoxjdon  campechianum;  Eucalyptus  gum  (Kino  Eucalypti),  obtained 
from  several  species  of  Eucalyptus;  Nut-gall  {Galla)  an  excrescence  on  one  of 
the  oaks  caused  by  the  jnmctures  and  ova  of  an  insect,  Cynips  Galla^  tinctoria. 
The.se  are  still  contained  in  the  pharmacopoeias,  but  promise  to  follow  a  large 
number  of  similar  bodies  which  have  been  discarded. 

Several  new  preparations  of  tannic  acid  have  been  introduced  into  thera- 
peutics of  late  years,  chiefly  for  use  as  intestinal  astringents.  Tannic  acid  itself 
is  liable  to  produce  irritation  of  the  stomach,  and  to  be  decomposed  or  ab- 
sorbed to  a  large  extent  before  it  reaches  the  large  intestine,  and  although 
the  cruder  prejxirations  are  less  liable  to  these  changes,  even  they  are  by  no 
means  devoid  of  disagreeable  features.  ]\leyer,  therefore,  introduced  (annigcn, 
or  diacetyltannin,  wliich  is  in.solublc  in  water  but  appears  to  be  dis.solved  in 
the  intestine;  and  there  to  act  like  tannic  acid.  Tannnform  and  tantiopin  are 
similar  compounds.  Tannalhin  is  a  combination  of  tannic  acid  and  albumen, 
dried  at  such  a  temperature  as  to  prevent  the  action  of  the  gastric  juice  upon  it, 
but  capable  of  being  broken  up  by  the  more  iH)werful  jjancreatic  fluid.  It  is 
entirely  insolul)le  and  is  not  asti'ingent  until  digested  in  the  bowel,  so  that  it 
has  no  irritant  action  on  the  stomacii  and  is  tasteless.  Taiinocol  is  a  combina- 
tion of  tamiic  acid  and  gelatin,  resembling  taniiali)in  in  most  respects.  The 
dose  of  these  artiiicial  compounds  is  0.5-2  G.  (10-30  grs.)  in  powder. 


VEGETABLE  ASTRINGENTS  11,3 

Several  combiiiatious  of  gallic  acid  have  been  introduced  of  late  years  as 
astringents,  but  they  are  merely  inert  protective  powders. 

Therapeutic  Uses. — The  preparations  of  tannic  acid  ought  to  be  used 
for  their  local  effects  exclusively.  They  are  applied  externally  in 
cases  of  excessive  secretion,  as  in  local  sweating  or  weeping  ulcers,  and 
occasionally  to  harden  the  skin.  For  this  purpose  tannic  acid  may  be 
used  in  solution  in  water,  or  in  the  form  of  the  glycerite  or  ointment, 
or  some  other  fluid  preparation  may  be  preferred.  A  similar  use  is 
made  of  the  metallic  astringents,  lead,  zinc,  and  alum  salts.  Tannic 
acid  is  used  as  a  mouth  wash  in  cases  of  swollen  gums,  or  relaxed 
throat,  and  may  here  be  prescribed  in  a  flavored  solution  or  in  the 
form  of  lozenges,  of  which  the  pharmacopoeia  offers  a  choice.  In 
certain  forms  of  diarrhoea  the  astringent  action  of  tannic  acid  is  of 
considerable  value,  and  occasionally  when  such  drugs  as  cod-liver 
oil  cause  diarrhoea,  tannic  acid  prevents  this  action  without  hindering 
their  general  effects.  The  pure  drug  is  seldom  used  in  these  cases, 
as  it  is  liable  to  derange  the  stomach  and  to  form  compounds  with  the 
albumins  before  it  reaches  the  bowel,  and  catechu,  krameria  or  kino 
is  accordingly  prescribed,  either  in  the  form  of  pills  or  in  fluid  prepara- 
tions ;  a  useful  preparation  is  the  compound  kino  powder,  which  com- 
bines the  astringent  action  of  tannin  with  the  specific  action  of  opium 
on  the  intestine  (compare  the  similar  preparations  of  lead  and  opium). 
Tannic  acid  stops  hemorrhage  by  precipitating  the  proteins,  when  it 
comes  into  immediate  contact  with  the  bleeding  point,  but  it  is  not 
of  so  much  value  for  this  purpose  as  some  of  the  metallic  astringents. 
When  the  bleeding  point  can  be  reached  directly  the  pure  acid  is  used, 
but  for  hemorrhage  of  the  intestine  or  stomach  one  of  the  extracts  is 
preferred.  Large  enemata  containing  tannic  acid  have  been  advised  in 
cholera,  dysentery,  and  similar  conditions. 

In  cases  of  poisoning  with  metals  and  alkaloids,  tannic  acid  is  often 
used  to  cause  their  precipitation  in  the  stomach,  but  the  tannate 
formed  must  be  removed  at  once,  as  it  is  gradually  dissolved  in  the 
digestive  fluids.  The  administration  of  tannic  acid  is  therefore  only 
a  temporary  expedient  to  allow  of  active  measures  being  taken  to 
empty  the  stomach. 

Some  individuals  are  peculiarly  susceptible  to  the  action  of  tannic 
acid,  which  induces  local  irritation  and  inflammation  wherever  it  is 
applied  in  these  cases. 

Bibliography. 

Hennig.    Arch.  f.  physiol.  Heilkunde,  xii,  p.  ,599. 
.    Lewin.    Virchow's  Archiv,  Ixxxi,  p.  74.     Deutsch.  med.  Woch.,  1904,  p.  803. 

Stockman.   Brit.  Mod.  Journ.,  1886,  ii,  p.  1077.    Arch.  f.  exp.  Path.  u.  Pharm.,  xl,  p.  147. 

Morner.    Ztschr.  f.  phys.  Chem.,  xvi,  p.  255. 

Heinz.     Virchow's  Archiv,  cxvi,  p.  220. 

Schatz.    Arch.  f.  exp.  Path.  u.  Pharm.,  xxvii,  p.  202. 

Meyer.    Deutsch.  med.  Woch.,  1894,  p.  626. 

Gottleib.    Ibid.,  1896,  p.  163. 

Rost.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxviii.  p.  346, 


114  Si- INSTANCES   ACTISa   LOCALLY 

Hainach.    Zcitschr.  f.  physiolog.  Chcniie,  xxiv,  p.  115. 
Flalow.     Dcutsch.  nicd.  Wcch.,  Thcrap.  Beilai;.,  1899,  p.  37. 
Slrauh.     Arch.  f.  cxp.  Path.  u.  Pharm.,  xlii,  p.  1. 
Gcbhardt.     Deutsch.  Arch.  f.  klin.  Med.,  Ixvi.  p.  585. 
Frey.    Arch.  f.  d.  ges.  Phys.,  oxxiii,  p.  491. 
Hesse,     ibid.,  cli,  p.  363. 

XI.     BILE. 

The  bile  is  very  sekloin  used  in  therapeutics  at  the  present  (hiy, 
although  it  was  formerly  credited  with  great  healing  virtues.  It  has 
a  bitter  taste,  and  may  have  some  effect  like  the  vegetable  bitters,  but 
has  no  advantage  over  these,  and  is  not  likely  to  be  used  to  promote 
the  appetite  now,  although  it  was  formerly  used  a  a  stomachic.  The 
bile  is  found  to  precipitate  the  peptones  in  test-tul)e  experiments,  but 
does  not  appear  to  retard  digestion  in  the  stomach  materially,  judging 
from  experiments  carried  out  in  a  case  of  gastric  fistula.  In  the  in- 
testine it  is  generally  believed  to  act  as  an  antiseptic,  chiefly  because 
the  stools  have  a  strong  ])utrefactive  odor  in  cases  of  retention  of  bile. 
Limbourg  has  also  shown  that  the  addition  of  bile  to  protein  solutions 
delays  their  decomposition,  while  there  is  some  evidence  that  it  pro- 
motes pancreatic  digestion.  It  has  some  purgative  action,  as  is  shown 
by  the  obstinate  constipation  which  often  occurs  when  it  is  prevented 
from  reaching  the  intestine;  according  to  Stadelmann,  the  bile  acids 
irritate  the  mucous  membrance  of  the  large  bowel  and  thus  induce 
purgation.  Some  of  the  drastic  purgatives  fail  to  act  in  the  absence  of 
bile,  apparently  because  they  are  not  dissolved  by  the  other  secretions 
(p.  90).  Bile  increases  the  activity  of  the  fat-splitting  ferment  of  the 
pancreas  and  thus  augments  the  absorption  of  fats,  but  it  is  doubtful 
whether  bile  given  by  the  mouth  has  this  action.  Most  of  the  bile 
given  by  the  mouth  is  absorbed  in  the  intestine  and  carried  to  the 
liver,  wiiich  excretes  it  again,  while  a  small  quantity  of  the  bile  acids 
escapes  in  the  urine.  In  the  liver  it  increases  the  secretion  of  both  the 
fluid  and  the  solids  of  the  bile;  in  fact,  the  bile  is  the  only  reliable 
cholagogue  known.  The  constituent  which  acts  on  the  secretory  liver 
cells  seems  to  be  the  bile  acids,  and  their  increase  is  greater  than  can 
be  accounted  for  merely  by  the  excretion  of  that  administered,  so  that 
it  would  seem  that  they  exercise  some  specific  stimulant  action  on  the 
secretory  cells.  The  bile  pigment  is  also  augumented  when  bile  acids 
are  absorbed,  owing  to  the  destruction  of  the  red  cells  of  the  blood,  as 
the  liberated  hirmoglobin  is  carried  to  the  liver  and  there  formed  into 
bile  pigment. 

liilc  given  bv  the  mouth  docs  not  cause  any  symptoms  oxt-ept  those  from 
the  iiitostino  aiid  liver.  Wlien  it  is  injected  into  tlio  blood,  however,  it  depresses 
the  central  nervous  system  and  the  lie;irt  muscle  from  its  (hrect  action  on  tlicsc 
organs,  and  dissolves" the  red  cells  of  the  l)loo(l  in  the  same  way  as  the  saponins, 
wliicli  it  reseml)l(>s  in  reducing  tlie  surface  tension.  Muscles  and  nerves  sus- 
pended in  a  solution  of  l)ile  salts  rapidly  lose  their  iirital)ility.  and  some  uni- 
ceUular  organisms  are  killed  and  dissolved  by  them.  The  ])oisonous  constituent 
of  the  bile  .seems  to  be  the  salts  of  the  bile  acids,  but  several  authors  have  stated 
that  the  pigment  is  also  active. 


ANTHELMINTICS  115 

Frascr  discovered  that  the  Ijile  acts  to  some  extent  as  an  antidote  to  the 
snake  venoms  through  its  containing  cholesterin,  which  retards  the  absorption  of 
the  venom;  it  is  nmch  more  efficient  when  it  is  mixed  with  the  poison  before  its 
apphcation,  tlian  when  it  is  injected  after  the  bite.  Others  have  found  tliat  the 
bile  of  animals  dying  of  an  infectious  disease  (rinderpest)  possesses  some  cura- 
tive properties  in  other  animals  suffering  from  the  same  malady,  this  being 
explained  by  the  excretion  of  the  antitoxin  in  the  bile. 

Bile  has  been  used  as  a  purgative,  and  it  has  been  particularly  recom- 
mended in  the  form  of  an  enema.  It  does  not  seem  to  be  reliable, 
however,  and  presents  no  advantages  over  soaps  and  similar  sub- 
stances. 

As  a  cholagogue  it  is  without  rival,  but  no  condition  is  known  in 
which  an  increase  of  the  bile  secretion  is  indicated,  for  though  it  has 
been  proposed  to  expel  gall-stones  by  raising  the  pressure  in  the  gall- 
ducts  by  cholagogues,  it  is  found  that  when  the  pressure  is  only  slightly 
increased,  the  secretion  is  arrested.  It  is  inconceivable  that  the  small 
rise  in  pressure  could  force  out  an  impacted  gall-stone. 

Bile  might  be  used  to  aid  the  absorption  of  fats,  particularly  when 
it  is  deficient  in  the  bowel;  in  a  case  of  biliary  fistula  Joslin  found  that 
much  less  fat  and  nitrogenous  food  escaped  in  the  stools  when  the 
patient  was  treated  with  bile  pills,  than  when  no  treatment  was  adopted. 

Preparations. 

Fcl  Bovis  (U.  S.  P.),  ox  gall,  the  fresh  bile  of  the  ox. 

Fel  Bovis  Purificatum  (U.  S.  P.),  Fd  Bovinum  Purificatum  (B.  P.),  is  formed 
from  the  fresh  bile  by  tlie  addition  of  alcohol,  filtration  and  evaporation  to 
pillular  consistency. 

Bile  is  always  prescribed  in  the  form  of  pills  made  from  the  purified  prep- 
aration.   0.5  G.  (7^  grs.);  B.  P.,  5-15  grs. 

Bibliography. 

Stadelmann.    Arch.  f.  exp.  Path.  u.  Pharm.,  xxxvii,  p.  352.  Ztschr.  f.  Biolog.,  xxxiv,  p.  1. 

Rywosch.     Arb.  a.  d.  pharm.  Instit.  zu  Dorpat,  ii,  p.  102;    vii.  p.  157. 

Liinbourg.     Ztschr.  f.  phys.  Chem.,  xiii,  p.  196. 

Pfaff  and  Balch.     Journ.  of  Exp   Med.,  ii,  p.  49. 

Fraser.    Brit.  Med.  Journ.,  1897,  ii,  pp.  125  and  595;    1898,  ii,  p.  627. 

Joslin.     Journ.  of  Exp.  Med.,  v,  p.  513. 

Cohnhewi.     Blochem.  Centralbl.,  i,  p.  171. 


XII.  ANTHELMINTICS. 

Anthelmintics  are  drugs  which  are  used  to  kill  or  remove  intestinal 
worms.  They  are  often  divided  into  vermicides  and  vermifuges, 
according  as  they  kill  or  merely  cause  the  expulsion  of  the  worm, 
but  this  is  determined  largely  by  the  quantity  which  comes  in  contact 
with  the  parasite  and  the  rapidity  with  which  the  bowel  is  evacuated. 

In  order  to  possess  any  value  as  an  anthelmintic,  a  drug  must,  of 
course,  act  more  strongly  on  the  parasite  than  on  the  host,  and  this 
more  intense  effect  may  be  attained  either  by  a  specific  action  on  the 
parasite,  or  by  the  drug  failing  to  be  absorbed  from  the  alimentary 


IIG  SUBSTANCES  ACTING  LOCALLY 

canal.  As  a  matter  of  fact,  the  anthelmintics  have  not  been  shown 
to  possess  any  such  specific  action,  but  seem  to  injure  most  forms  of 
living  matter;  this  has  been  demonstrated  more  particularly  for  muscle 
tissue.  Their  use  is  thus  rendered  possible  only  by  their  slow  absorp- 
tion which  permits  of  their  acting  on  the  parasite  in  greater  concen- 
tration than  on  any  of  the  tisues  of  the  host. 

Before  the  administration  of  an  anthelmintic,  the  bowel  ought  to  be 
emptied  of  its  contents  as  far  as  possible  by  a  light,  easily  digested 
diet  and  a  laxative,  and  a  brisk  purge  ought  to  follow  some  hours 
later,  in  order  to  remove  the  dead  or  stupefied  worm.  The  anthel- 
mintic is  often  prescribed  along  with  a  purge. 

A  number  of  drugs  belonging  to  other  groups  are  used  occasionally 
as  anthelmintics.  Thus  several  of  the  volatile  oils — tansy,  turpentine — 
have  some  reputation;  and  chloroform  is  also  administered  occasionally 
by  the  mouth  for  its  action  on  the  parasites,  but,  like  the  volatile  oils, 
is  apt  to  produce  gastric  and  intestinal  irritation.  The  less  easily 
absorbed  antiseptics,  such  as  naphthol,  have  been  used  with  good 
results.  Large  enemata  of  salt  solutions,  or  of  infusion  of  quassia, 
are  thrown  into  the  rectum  when  the  worms  infest  the  large  intestines. 
Many  other  drugs  enjoy  some  popular  reputation  as  "worm-cures," 
but  have  proved  inferior  to  the  recognized  remedies. 

Male  fern,  cusso  and  pomegranate  are  those  most  largely  used  for 
tapeworm;  thymol  has  been  used  with  great  success  in  hookworm 
(uncinariasis)  while  santonin  is  the  chief  anthelmintic  in  infection  with 
round  worm. 

1.  Male  Fern  (Aspidium,  Filix-mas). 

A  number  of  ferns  contain  bodies  which  present  considerable  resem- 
blance to  each  other  from  a  chemical  as  well  as  from  a  pharmacological 
point  of  view,  and  which  may  therefore  be  classed  together,  at  any 
rate  until  further  information  is  available  regarding  them.  The  best 
known  of  these  is  the  male  fern  (Aspidium,  Filix-mas). 

The  active  constituent  of  this  remedy  was  supposed  to  be  Filicic  Acid  by 
Poulsson,  l)ut  lioelini  has  found  other  neutral  and  acid  l)odies  present,  Asi>i(l- 
inin,  Flavaspidic  Acid,  Alhasi)idi7i,  and  Aspidinol — and  Kraft  has  added 
Filmaron  and  Flavai^pidinin.  These  l)odics  are  all  derivatives  of  phloroglucin 
and  butyric  acid,  and  it  is  still  uncertain  whether  the  efiects  of  male  fern  are 
to  be  attributed  to  any  one  of  them  or  whether  all  of  them  may  not  shar(>  in 
the  action.  Jucquet  liolds  that  the  chief  therapeutic  factor  is  the  filmaron,  but 
that  tlie  others  also  have  some  effect.^ 

Action. — The  extract  or  oleoresin  of  male  fern,  which  is  the  only 
one  of  these  {)lants  used  in  regular  medicine,  as  a  general  rule  passes 
through  the  bowel  without  causing  any  symptoms  whatever.  The 
quantity  of  active  substance  dissolved,  while  sufficient  to  destroy  the 

'  Nearly  related  bodies  have  been  found  in  Aspidium  athaniantieuni  (Unconioconio), 
whieh  contains  two  forms  of  Pannic  Acid,  and  in  Aspidium  spintilosum,  while  smaller 
quantities  of  acids  occur  in  a  large  immlier  of  ferns.  Several  of  these  ferns  enjoy  a  repu- 
tation as  anthelmintics  for  tapeworm,  and  their  \irtues  are  generally  considered  due  to 
these  bodies. 


ANTHELMINTICS  117 

l)arasite,  is  too  small  to  produce  any  effects  on  the  host,  and  escapes 
with  the  other  contents  of  the  bowel,  or  if  absorbed  does  not  cause 
any  synii)tonis.  In  rare  cases,  however,  where  large  (juantities  are 
administered,  or  where  some  unknown  conditions  favor  the  absorption 
and  retention  of  an  unusually  large  amount  of  the  active  constituents, 
grave  and  even  fatal  symptoms  may  supervene.  These  consist  in 
vomiting  and  purging,  with  acute  pain  in  the  abdomen,  muscular 
weakness,  confusion  and  somnolence,  with  occasional  twitching  of  the 
muscles,  or  slight  convulsive  movements,  collapse,  coma,  and  death. 
The  stomach  and  intestine  are  found  congested  and  swollen,  and  some- 
times covered  with  small  ecchymoses.  In  some  cases  icterus  has  been 
observed  to  follow  the  administration  of  male  fern,  probably  from  the 
duodenal  catarrh,  but  possibly  from  destruction  of  the  red  blood  cells 
the  number  of  which  has  been  found  to  be  diminished  in  some  instances 
(Georgiewsky) .  In  other  cases  permanent  or  temporary  blindness  has 
resulted  from  neuritis  and  subsequent  atrophy  of  the  optic  nerve. 

In  the  rabbit,  filicic  acid  produces  very  similar  symptoms.  The  congestion 
of  the  stomach  and  intestine  is  evidently  due  to  the  local  irritation  produced 
by  the  poison,  while  the  other  symptoms  point  to  changes  induced  in  the  cen- 
tral nervous  system.  The  spinal  cord  is  stimulated,  for  the  reflex  excitability 
is  increased,  but  the  higher  parts  of  the  central  nervous  system  seem  to  be 
depressed,  and  the  paralysis  of  the  respiratory  centre  is  the  cause  of  death, 
although  the  heart  is  also  weakened  by  fihcic  acid.  Inflammation  of  the  kidney 
is  said  by  some  authors  to  occur,  and  in  some  cases  Poulsson  found  evidence 
of  glycuronic  acid  in  the  urine. 

In  the  frog,  a  mixture  of  depression  and  stimulation  of  the  central  nervous 
system  is  produced  by  filicic  acid,  along  with  distinct  diminution  in  the  strength 
of  the  skeletal  muscles  and  the  heart. 

Aspidin  (from  Aspidium  spinulosum)  causes  dyspnoja  and  paralysis  of  the 
spontaneous  and  respiratory  movements  in  frogs;  fibrillary  twitching  of  the 
muscles  sets  in  after  some  time  and  is  succeeded  by  con\ailsive  movements  or 
tonic  spasms,  which  indicate  an  increased  activity  of  the  reflexes  of  the  spinal 
cord.  The  heart  is  de^Dressed  and  eventually  paralyzed,  and  the  peripheral 
muscles  are  also  weakened.  The  muscular  tissue  of  the  invertebrates  is  more 
powerful!}^  affected  by  the  constituents  of  male  fern,  and  Straub  attributes  its 
action  on  the  tapeworm  to  its  paralyzing  muscle.  Mammals  do  not  seem  to 
be  affected  by  aspidin  injected  h^vpodermically  or  administered  by  the  mouth, 
but  when  it  is  introduced  directly  into  the  bloodvessels,  it  proves  fatal  by 
paralyzing  the  respiratory  centre.  Aspidinin  induces  very  similar  sjanptoms 
in  the  frog,  while  the  other  constituents  are  less  active. 

The  blindness  which  has  been  observed  in  some  cases  of  male  fern  poison- 
ing has  also  been  produced  in  dogs;  it  occurs  chiefly  in  young,  weakly,  and 
anaemic  individuals. 

Pannic  acid  differs  from  filicic  chiefly  in  its  acting  more  strongly  on  muscle 
and  less  on  the  central  nervous  system  of  the  frog. 

Preparations. 

Aspidium  (U.  S.  P.),  Filix-mas  (B.  P.),  Male  fern,  the  rhizome  of  Dryopteris 
Filix-mas  and  of  Dryopteris  marginalis. 

Oleoresina  Aspidii  (U.  S.  P.),  2  G.  (30  grs.). 

ExTRACTUM  FiLicis  LiQuiDUM  (B.  P.)  Contains  20  per  cent,  of  active  princi- 
ples, 45-90  mins. 

These  are  practically  identical  in  composition;  the  first  is  an  acetone,  the 
second  an  ether  extract. 


n.S  SUBSTANCES  ACTING  LOCALLY 

Therapeutic  Uses. — Male  fern  is  used  exelusively  in  the  treatment  of 
tapeworm  aiul  of  Aiicliylostonmm  duodenale.  Previous  to  its  admin- 
istration the  })()\vel  ()U<i;lit  to  l)e  emptied,  as  far  as  possible,  by  a  mod- 
erately light  diet  for  one  or  two  days  and,  where  neeessary,  by  a 
purgative.  The  oleoresin,  or  licjuid  extract,  is  then  to  be  administered 
in  the  form  of  i)ills  or  enclosed  in  a  capsule  or  suspended  in  nmcilage, 
and  another  purgative  is  required  some  G-12  hours  later.  In  case 
the  parasite  fails  to  be  dislodged,  several  days  ought  to  be  allowed  to 
elapse  before  a  second  dose  is  given.  Poulsson  recommends  that  oily 
substances  be  avoided  during  the  "cure,"  as  they  dissolve  the  active 
bodies,  and  thus  promote  their  absorption.  Other  authorities  dispute 
this  view  and  some  consider  that  oils  in  dissolving  the  active  principles 
render  them  more  poisonous  to  the  parasites,  but  it  is  certainly  sug- 
gestive that  in  many  cases  of  poisoning  with  male  fern  castor  oil  had 
been  given  along  with  it  or  soon  after.  Marked  anaemia,  general  debility 
and  chronic  alcoholism  seem  to  predispose  to  male-fern  poisoning,  and 
the  drug  is  accordingly  to  be  used  with  care  in  these  conditions. 

Bibliography. 

Poulsson.    Arch.  f.  exp.  Path.  u.  Pharm.,  xxix,  p.  1;   xxxv,  p.  97;   xh',  p.  246. 

Robert.     Therap.  Monatsheft,  1893,  p.  136. 

Birch-Hirschfeld.     Graefe's  Arch.  f.  Ophthalmologic,  1.,  p.  22.5. 

Jacquet.     Therap.  Monatsheft,  August,  1904. 

Georgioxosky.    Ziegler's  Beitriige,  xxiv,  p.  1. 

Boehm.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxv,  p.  1;    xxxviii,  p.  35. 

tSiraub.     Ibid.,  xlviii,  p.  1. 

Walko.     Deutsch.  Arch.  f.  klin.  Mod.,  Ixiii,  p.  348! 

2.  Cusso. 

Cusso,  or  Kousso,  contains  a  neutral  body,  Kosoto.vin,  which  is 
soluble  in  alcohol  and  in  alkaline  fluids,  but  is  insoluble  in  water;  it  is 
a  compound  of  ])hlor()glucin  and  butyric  acid  like  the  constituents 
of  male  fern,  wliich  it  resembles  somewhat  in  its  pharmacological 
action. 

Cusso  has  a  bitter,  somewhat  astrigent  taste,  and  sometimes  causes 
nausea  and  vomiting  and  some  looseness  of  the  bowels.  In  rare  cases 
prostration  and  collapse,  with  irr(>gularity  of  the  pulse,  are  said  to 
have  occurred  from  its  use. 

In  the  frop;,  kosotoxiii  ])aralyzos  the  ncrvo  ends  like  ourara,  and  has  a 
specific  action  on  tiic  stripcHl  muscular  tissue,  whicli  it  weakens  and  eventually 
jjaralyzes.  The  lieart  inu.scle  luuieri^oes  similar  chanjjjes.  In  manunals  the 
nmscular  action  is  well  developed,  but  is  accom])anied  by  some  stimulation  of 
the  medullary  centres,  indicated  by  rapiil,  dyspnceic  breathing,  salivation  and 
vomiting.  The  stools  are  often  fluid,  and  the  urine  is  increa.sed  in  amount. 
When  it  is  injected  directly  into  the  cinailation,  some  convulsive  movements 
are  often  observed,  and  the  lieart  is  weakened  and  paralyzed.  Kosotoxin 
seems  to  he  a  general  iJrotoplasm  poi.son,  as  is  inilicateil  liy  its  .Mctioii  on  nnisde. 
and  by  its  retarding  (he  growth  of  yeast. 


ANrilELMINTICS  119 


Preparations. 

CUSSO  (V.  S.  P.,  B.  P.),  (Kousso  or  Hraycni),  the  pistill.-ilc  flowcM-s  of  1  Infivnia 
Al)y8siiiica  (Hniyeni  aiitlielininiica). 

Cusso  is  sfuerally  given  by  suspending  15  G.  (§  oz.)  of  the  powdered  flowers 
in  water.  Kosotoxin  has  not  yet  been  prescribed  for  tlierajieutic  purjioses. 
The  usual  preliminary  treatment  ought  to  be  instituted,  but  no  purge  is  icquired 
after  Cusso  as  a  general  rule.  It  is  used  exclusively  as  an  anthelmintic  in  cases 
of  tapeworm. 

Bibliography. 

Leichsenring.     Arch.  d.  Pharm.,  ccxxxii,  p.  50. 
Handniann.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxvi,  p.  138. 

3.  Pelletierine. 

The  bark  of  the  pomegranate  contains  a  very  large  amount  of  tannic 
acid  (20-25  per  cent.),  along  with  several  alkaloids,  of  which  PeUe- 
tierine,  or  Funicine,  and  Isopunicitie  alone  are  active  in  ordinary  doses. 
All  the  pomegranate  alkaloids  are  closely  related  chemically  to  each 
other  and  to  tropine  (see  atropine).  None  of  them  can  be  classed 
among  the  more  active  poisons  as  far  as  man  and  the  higher  animals  are 
concerned. 

In  man,  large  doses  cause  heaviness,  confusion,  giddiness,  and  very 
marked  weakness  of  the  limbs.  The  consciousness  is  but  little  affected 
but  the  sight  is  often  dim  and  uncertain,  and  in  one  case  complete 
blindness  persisted  for  several  days.  Occasionally  nausea  and  dis- 
comfort in  the  abdomen  are  complained  of,  and  more  rarely  vomiting, 
tremors,  and  cramps  of  the  leg  muscles  are  produced;  the  gastric 
symptoms  are  perhaps  due  to  the  large  quantity  of  tannic  acid  in  the 
drug  rather  than  to  the  alkaloids. 

In  the  frog  and  in  most  mammals,  pelletierine  causes  a  distinct  increase  in 
reflex  irritability  of  the  spinal  cord  and  medulla  oblongata,  along  with  some 
depression  of  the  higher  divisions  of  the  central  nervous  system.  Very  large 
doses  weaken  or  paralyze  the  conductivity  of  the  nerve  plates  in  the  frog, 
like  curara.  The  heart  muscle  is  also  acted  on  and  its  pulsations  are  slowed  in 
the  frog,  although  they  may  be  temporarily  augmented  in  force. 

Pelletierine  and  isopunicine  have  a  specific  action  on  tapeworms, 
for  Schroeder  found  that  a  solution  of  one  part  in  1  (),()()()  was  sufficient 
to  kill  them  in  ten  minutes,  while  a  stronger  solution  had  practically 
no  effect  upon  other  intestinal  worms. 

Preparations. 

Granatum  (U.  S.  P.),  Pomegranate,  the  bark  of  the  stem  and  root  of  Punica 
Granatum  2  G  (30  grs.) 

Fluidextractum  Granati  (U.  S.  P.),  2  c.c.  (30  mins.). 

Pelletierinre  Tannas  (U.  S.  P.,  B.  P.),  a  mixture  in  varying  proportions  of 
the  tannates  of  four  alkaloids  (punicine,  isopunicine,  metliylpunicine  anil 
pseudopunicine),  obtained  from  pomegranate  bark.  Dcse,  0.25  G.  (4  grs.); 
B.  P.  2-8  grs. 


120  SUBSTANCES  ACTING  LOCALLY 

Therapeutic  Uses.— Granatum  is  used  exclusively  as  an  anthelmintic, 
and  the  crude  bark  has  now  been  displaced  almost  entirely  by  the 
tannate.  The  preliminary  treatment  is  the  same  as  that  given  under 
aspidium,  and  a  i)urge  ought  to  be  given  1-2  hours  after  the  vermicide. 

Bibliography. 

Dujardin-Beaumelz.     Bull,  de  Therap.,  xcviii,  p.  433. 

Berenger-Feraud.     Ibid.,  xcvii,  pp.  8,  337,  391. 

r.  Schroeder.    Arch.  f..exp.  Path.  u.  Pharm.,  xviii,  p.  381,  and  xix,  p.  200. 

Heme.    Pfliiger's  Archiv,  xcii,  p.  464. 

Kamala  is  a  reddish-brown  powder  which  consists  of  the  minute  glands  and 
hairs  obtained  from  the  surface  of  the  fruits  of  IVIallotus  Phihppensis.  It 
contains  two  or  more  substances  which  have  been  termed  Kamalin,  Rotllerin, 
or  Mallotoxin,  and  which  are  probably  neutral  bodies  lil<e  kosotoxin,  but  it  is 
not  known  which  of  these  is  the  active  constituent.  Kamala  is  used  in  cases 
of  tapeworm  in  doses  of  2-8  G.  (30  grs.-i  oz.)  suspended  in  water.  It  acts 
as  an  intestinal  irritant,  causing  purging  and,  more  rarely,  nausea  and  vomit- 
ing. No  purge  is  necessary,  therefore,  after  the  powder.  An  alcoholic  tinc- 
ture of  kamala  has  been  found  quite  as  efficient  as  the  powder. 

Areca  Nut,  the  seeds  of  the  palm  Areca  Catechu,  is  used  in  veterinary  medi- 
cine as  a  remedy  in  tapeworm.  It  contains  a  fluid  alkaloid  arecoline  (C8H13NO2), 
which  resembles  pilocarpine  in  action.  In  addition,  it  contains  several  inactive 
alkaloids  and  tannic  acid. 

4.  Thymol. 

Thymol  (C10H14O)  is  a  crystalline  substance  obtained  from  the 
volatile  oil  of  Thyme  and  other  plants,  and  chemically  is  a  homologue 
of  phenol.  It  is  very  insoluble  in  water  and  when  taken  in  solid  form 
appears  to  be  absorbed  from  the  alimentary  tract  with  difficulty. 

In  man,  thymol  has  caused  depression,  nausea,  vomiting,  headache 
and  confusion  with  roaring  sounds  in  the  ears  and  alarming  weakness 
of  the  heart  resulting  in  giddiness  and  collapse.  Its  irritant  action  on 
the  mucous  membrane  may  cause  burning  sensations  in  the  stomach 
and  vomiting. 

In  poisoning  in  animals  it  induces  a  condition  of  w'eakness  and 
apathy  which  passes  into  collapse  and  death,  generally  without  any 
convulsions.  Fatty  degeneration  of  the  liver,  congestion  or  even 
consolidation  of  the  lungs,  and  irritation  of  the  intestine  are  found 
pDstniorteni.  It  is  much  less  irritant  than  carbolic  acid,  and  is  said  to 
be  a  more  pow^erful  germicide.  Thymol  is  excreted  in  the  urine  in 
combination  wnth  sulphuric  and  glycuronic  acid;  it  is  said  to  have 
caused  renal  irritation  in  some  cases  as  shown  by  the  appearance 
of  albumin  and  even  of  blood  in  the  urine. 

Thymol  (U.  S.  P.,  B.  P.)  (CCII3C3H7CH3OH)  occurs  in  common  th^^ne  and 
otlitT  plants,  and  forms  large  colorless  crystals  which  have  the  odor  of  lliyme 
and  are  very  insoluble  in  water.  The  pliarmacopceitu?  give  the  dose  as  0.125  G. 
(2  grs.),  but  in  liook-worm  disease  it  is  given  up  to  2  G.  (30  grs.) 

Tli\  luol  was  used  at  om>  time  in  ,'„  per  cent,  solution  as  an  antiseptic 
lotion  and  also  as  a   month  wash   or   gargle.     It  has  also  been  given 


ANTHELMINTICS  121 

as  an  internal  antiseptic  in  acute  rheumatism,  typhoid  fever  and  tuber- 
culosis, but  without  success.  At  present  it  is  used  widely  as  an  anthel- 
mintic in  hook-worm  disease  (anchylostomiasis  or  uncinariasis);  it  is 
given  in  capsules  or  emulsions  in  doses  of  30  grains  repeated  in  two 
hours  and  followed  in  six  or  eight  hours  by  a  brisk  saline  purge.  The 
bowel  should  be  emptied  as  far  as  possible  by  light  diet  and  an  aperient 
before  the  treatment  is  begun. 

Bibliography. 

Husemann.     Arch.  f.  exp.  Path.  u.  Pharm.,  iv,  p.  280. 

Blum.    Zts.  f.  physioL  Chem.,  xv    p.  514.     Deutsche  med.  Woch.,  1891,  p.  186. 

Lewin.     Virchow's  Archiv,  Ixv,  p.  164. 

Baelz.     Arch,  der  Heilkunde,  xviii,  p.  60. 

Schultz.     Journ.  Amer.  Med.  Asso,.  1911,  ii,  p.  1102. 

5.  Santonin. 

Santonin  (CisHisOs)  is  an  anhydride  of  santonic  acid,  a  derivative 
of  naphthalene.  It  occurs  in  Artemisia  pauciflora  along  with  a  nearly 
related  body  (artemisin)  and  a  volatile  oil  (cineol).  Santonin  is  very 
insoluble  in  water,  but  is  dissolved  by  alkalies,  with  which'  it  forms 
santonates. 

Action.— Owing  to  its  insolubility  in  water,  santonin  has  only  a 
slightly  bitter  taste  in  the  mouth.  It  is  partially  dissolved  in  the 
stomach  and  passes  into  the  bowel  where  it  effects  the  removal  of  some 
forms  of  intestinal  worms.  Under  special  conditions  part  of  the  santonin 
may  be  absorbed  in  the  bowel,  however,  and  general  poisoning  results 
without  the  parasites  being  affected.  A  certain  amount  of  absorption 
occurs  in  every  case,  as  is  shown  by  the  disorders  of  color  vision  and 
by  the  yellow  coloration  of  the  urine.  At  first  objects  appear  of  a  bluish 
color  to  the  patient,  but  this  aberration  is  of  comparatively  short  dura- 
tion and  may  in  fact  pass  unnoticed.  It  is  followed  by  a  much  longer 
period  of  "yellow  sight"  or  xanthopsia,  during  which  objects  that  are 
brightly  illuminated  seem  to  have  a  yellow  tinge,  blue  seems  green, 
and  violet  is  indistinct,  although  in  dimmer  lights  the  violet  may  still 
predominate.  In  severe  poisoning  the  appreciation  of  the  darker  colors 
becomes  very  imperfect,  and  violet  and  even  blue  may  fail  to  be  dis- 
tinguished from  black.  In  general  the  violet  end  of  the  spectrum  is 
shortened,  while  the  yellow  impresses  the  retina  more  vividly  than 
normally.  In  some  cases  the  senses  of  taste  and  smell,  and  more  rarely 
the  hearing  are  also  deranged.  These  symptoms  all  pass  off  in  the 
course  of  a  few  hours,  a  second  stage  of  "violet  sight"  occasionally 
intervening  before  complete  recovery. 

The  symptoms  produced  by  the  absorption  of  large  quantities  of 
santonin  are  so  uniform  in  man  and  the  other  mammals  that  it  is  suffi- 
cient to  enumerate  those  observed  in  experiments  on  the  dog.  The 
first  distinct  effects  are  generally  twitching  of  the  muscles  of  the  head, 
frequently  beginning  on  one  side.  These  are  followed  by  rolling  of 
the  eyes,  grinding  of  the  teeth,  flexion  and  extension  of  the  neck  and 


122  SirnSTANCES  ACTIXG  LOCALLY 

rotation  of  the  head  from  side  to  side,  later  by  regular  epileptiform  con- 
vulsions in  which  the  animal  is  first  thrown  into  opisthotonos  and  then 
into  clonic  spasms  of  the  limbs  and  trunk.  These  are  interrn])ted  by 
intervals  of  repose  during  which  a  curious  momentary  contraction  of  all 
the  muscles  of  the  l)ody  is  often  noticed.  During  the  convulsive  seizures 
the  respiration  is  irregular  and  insufficient,  and  in  fatal  cases  it  fails 
to  return  after  the  convulsion  passes  off,  and  the  animal  dies  of  as- 
phyxia. In  man,  some  confusion,  nausea  and  vomiting  occasionally 
occur  after  quantities  which  are  too  small  to  produce  convulsions,  and 
in  several  cases  aphasia  has  been  observed.  In  frogs,  convulsions  are 
produced  by  santonin  as  in  mammals,  but  they  are  preceded  by  a 
prolonged  stage  of  depression,  which  is  entirely  absent  in  the  higher 
animals. 

These  symptoms  manifestly  point  to  changes  in  the  central  nervous 
system.  The  xanthopsia  is  generally  referred  to  a  specific  action  on 
the  retina,  though  some  hold  that  the  central  apparatus  of  vision  in 
the  brain  is  the  seat  of  the  action.  The  condition  has  been  ascribed 
to  a  preliminary  stimulation  and  subsequent  depression  of  the  sense 
organs  for  the  perception  of  the  violet  and  eventually  of  the  blue  rays 
of  the  spectrum,  or  more  precisely  to  some  obstruction  to  the  regener- 
ation of  the  substance  in  the  retina  which  normally  appreciates  violet 
rays  (Filehne).  The  clonic  nature  of  the  convulsions  at  once  points 
to  an  aflFection  of  the  brain  rather  than  of  the  cord,  and  the  epileptiform 
convulsions  are  generally  regarded  as  arising  from  stimulation  of  the 
cortex  in  the  higher  animals  and  man,  though  the  basal  cerebral  ganglia 
may  also  be  involved ;  the  sudden  contractions  observed  in  the  intervals 
of  repose  are  ascribed  to  stimulation  of  the  gray  matter  in  the  region 
of  the  pons.  Although  these  parts  of  the  central  nervous  system  are 
the  most  susceptible  to  the  action  of  santonin,  large  quantities  also 
affect  the  cord  after  division  of  the  medulla  oblongata  and  produce 
tonic  convulsions  resembling  those  seen  in  strychnine  poisoning. 

The  medullary  centres  seem  to  be  comparatively  little  afi'ected  by 
santonin,  the  respiration  being  interfered  with  during  the  spasms,  but 
returning  to  its  ordinary  rate  and  strength  during  the  intervals.  The 
circulation  is  altered  only  by  the  asphyxia,  and  the  heart  continues  to 
beat  long  after  the  respiration  has  ceased. 

Santonin  undergoes  some  oxidation  in  the  tissues  and  is  excreted  in 
the  faeces  and  urine  in  several  forms,  two  of  which  have  been  examined 
by  Jaffe  and  found  to  be  oxysantiMiins.  The  urine  and  sometimes 
the  fjcces  have  a  deep  yellow  color,  which  changes  to  red  or  purj)le 
when  alkalies  are  added.  A  similar  reaction  is  obtained  from  the  urine 
after  the  administration  of  chrysophanic  acid,  as  in  rhubarb  or  senna. 

Santonin  is  universally  used  as  a  remedy  for  the  round  worm,  Ascaris 
liunl)ric()i(h's,  and  most  dinicians  believe  that  it  has  a  specific  poisonous 
action  on  these  animals,  and  that  its  undoubted  effects  are  due  to  its 
kilhng  them.  In  experiments  on  the  entozoa  outside  the  body,  however, 
\-on  Schroeder  found  that  santonin  solutions  were  by  no  means  fatal 
to  them,  and  he  exjjlains  tiieir  therapeutic  effects  by  supposing  that 


I 


ANTHELMINTICS  123 

santonin  renders  tlie  intestine  so  unpleasant  an  alxxle  for  the  parasites 
that  they  migrate  from  it  voluntarily  into  the  large  bowel,  and  are 
carried  out  by  the  purgative.  The  worms  are  often  found  in  active 
movement  when  passed  after  santonin,  although  this  movement  ceases 
very  soon  afterward  from  the  exposure  to  cold. 

The  santonates  act  in  precisely  the  same  way  as  santonin,  but  are  less  suit- 
!il)le  as  anthelmintics,  owing  to  their  greater  solubility  and  rapid  absorption. 

Preparations. 

Santoninum  (U.  S.  p.,  B.  P.),  CisHisOs,  a  neutral  principle  derived  from 
Artemisia  pauciflora,  is  colorless  when  freshly  prepared,  but  assumes  a  yellow 
color  when  exposed  to  the  light.  This  does  not  seem  to  impair  its  activit^y 
materiall}',  but  it  is  preferable  to  avoid  it  by  keeping  santonin  in  amber-colored 
vials.    Dose,  0.065  G.  (1  gr.);   B.  P.,  1-3  grs. 

Trochiscus  Santonini  (B.  p.),  each  containing  1  gr. ;  (U.  S.  P.),  ^  gr. 

Therapeutic  Uses. — Santonin  is  used  almost  exclusively  to  remove 
Ascaris  lumbricoides  from  the  intestine.  It  is  much  less  effective 
against  tapeworm  or  other  intestinal  parasites.  It  may  be  prescribed 
as  a  powder,  or  lozenge,  or  in  solution  in  oil. 

The  bowel  ought  to  be  emptied  by  suitable  diet  and  a  laxative  before 
the  santonin  is  administered,  and  a  sharp  purge  ought  to  be  given  two 
to  four  hours  afterward  in  order  to  bring  away  the  entozoa. 

Santonin  has  been  advised  in  some  retinal  diseases,  but  the  results 
have  generally  been  unsatisfactory. 

Bibliography. 

Binz.    Arch.  f.  exp.  Path.  u.  Pharm.,  vi,  p.  300. 

Lewin.    Berl.  klin.  Woch.,  1883,  p.  170. 

Luchsinger.     Pfliiger's  Archiv,  xxxiv,  p.  293. 

Jaffe.    Ztschr.  f.  klin.  Med.,  xvii.     SuppL,  p.  7.    Ztschr.  f.  phys.  Chom.,  xxii,  p.  538. 

Kramer.     Ztschi'.  f.  Heilkunde,  xiv,  p.  303. 

Tnrtschaninow.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxiv,  p.  208. 

V.  Schroeder.     Ibid.,  xix,  p.  290. 

Nagel.     Ztschr.  f.  Psychol,  u.  Phys   d.  Sinnesorgane,  xxvii.  p.  267. 

Harnack.    Zts.  f.  klin.  Med.,  xxv,  p.  16;  Arch.  f.  exp.  Path.  u.  Pharm.,  xlvi,  pp.  272,  447. 

72o.se.    Virchow's  Archiv,  xvi,  p.  233;  xviii,  p.  15;  xix,  p.  522;  xx,  p.  245;  xxviii,  p.  30. 

Hiifner.     Arch.  f.  Ophthalmol,  xiii,  p.  309. 

Filehne.     Pfliiger's  Archiv,  Ixxx,  p.  96. 

Spigelia. 

_  Another  remedy  used  in  cases  of  round  worm  is  pink  root,  Spigelia  mari- 
tima,  the  active  principle  of  which  is  unknown,  although  an  alkaloid,  spige- 
line,  is  said  to  occur  in  it.  Occasional  cases  of  j^oisoning  have  been  observed, 
especially  in  children,  the  symptoms  consisting  in  flushing  and  dryness  of  the 
skin,  often  with  some  oedematous  swelling  of  the  face,  delirium  and  sopor 
followed  by  dimness  of  sight  or  temporary  blindness.  In  frogs  spigelia  ap- 
pears to  depress  the  brain  and  spinal  cord,  and  the  heart  beats  more  slowly 
and  weakly,  while  in  rabbits  the  most  prominent  symptoms  arise  from  the 
breathing,  which  becomes  slow  and  labored  and  finally  ceases  in  a  convulsive 
attack.     In  the  dog  and  cat  its  injection  is  followed  by  vomiting,  great  weak- 


124  SUBSTANCES  ACTING  LOCALLY 

ness  and  incoordination  of  the  movements,  restlessness,  rapid  dj^spnoeic  res- 
piration and  finally  by  stupor,  coma  and  death  from  failure  of  the  respiratory 
centre. 

Spigelia  (U.  S.  P.),  the  rhizome  and  roots  of  vSpigelia  marilandica. 

Fluidexlr actum.  SpigelicE  (U.  8.  P.),  4  c.c.  (1  fi.  dr.). 

The  fluidextract  is  used  to  remove  round  worms,  which  it  seems  to  effect 
in  very  much  the  same  way  as  santonin.  It  ought  to  be  preceded  and  followed 
by    a    purge. 


Xm.   ANTISEPTICS  AND  DISINFECTANTS. 

Various  balsams,  tars  and  other  aromatic  bodies  have  long  enjoyed 
a  certain  reputation  in  the  treatment  of  wounds,  but  the  whole  course 
of  surgery  was  changed  about  1870  when  Lister  introduced  the  system- 
atic application  of  antiseptics  to  wounded  tissues.  The  general  principle 
underlying  this  treatment  was  that  infection  arises  from  the  invasion 
of  the  tissues  by  microorganisms  and  that  it  can  be  combated  either 
by  preventing  them  from  reaching  a  wound  or  by  retarding  their  growth 
on  the  injured  surface  by  means  of  antiseptic  drugs.  The  first  of  these 
which  he  introduced  was  carbolic  acid,  and  this  held  its  position  unchal- 
lenged for  several  years,  when  it  was  discovered  that  manj^  other 
substances  were  equally  destructive  to  the  microorganisms  and  were 
less  poisonous  to  the  invaded  tissues.  Of  late  years  the  tendency  has 
been  rather  to  prevent  the  infection  of  the  tissues  by  careful  manipula- 
tion (asepsis),  but  when  this  is  impossible  the  use  of  antiseptics  and 
disinfectants  is  still  necessary,  and  even  the  new^er  aseptic  surgerj' 
depends  in  part  on  the  use  of  disinfectants  to  cleanse  the  skin  and 
instruments. 

A  disinfectant  in  the  strict  use  of  the  term  is  a  substance  used  to 
destroy  microbes,  while  an  antiseptic,  while  not  actually  killing  the 
germs,  prevents  their  growth  as  long  as  it  remains  in  contact  with 
them.  A  disinfectant  is  accordingly  only  intended  to  act  for  a  short 
time,  for  if  the  infected  matter  be  once  rendered  sterile  it  can  onh- 
become  dangerous  by  being  again  contaminated.  For  example,  a 
room  requires  only  to  be  disinfected  after  a  case  of  infectious  disease. 
A  w^ound,  on  the  other  hand,  even  though  completely  disinfected  may 
become  contaminated  again  very  easily  and  an  antiseptic  may  be 
required  to  prevent  the  further  growth  of  microbes.  INIany  sub- 
stances are  disinfectant  in  large  quantities  and  antiseptic  in  more 
dilute  solutions,  but  others  are  too  weak  to  disinfect  thoroughly  though 
they  retard  the  growth  of  pathogenic  organisms,  and  still  others  may 
be  employed  to  disinfect  but  are  unsuitable  for  use  as  antiseptics, 
either  because  they  are  too  poisonous  to  be  applied  for  a  sufficient 
time,  or  because  they  lose  their  activity  on  contact  with  living  matter 
(e.  g.,  oxidising  disinfectants). 

A  very  large  number  of  substances  possess  disinfectant  properties, 
that  is,  are  capable  of  destroying  microbes  when  they  can  be  ajiplicd 
in  sufficient  quantity.  They  have  no  specific  action  on  the  microbes, 
iiowever,  but  act  as  general  protoplasm  poisons  destroying  living  tissue 


ANTISEPTICS  AND  DISINFECTANTS  125 

of  all  kinds  wherever  they  come  in  contact  with  it.  On  the  other  hand, 
drugs  such  as  strychnine,  which  act  on  specialized  parts  of  the  vertebrate 
organism  and  have  less  effect  on  the  less  differentiated  tissues,  are 
equally  harmless  to  the  undifferentiated  protoplasm  of  the  microbes.  It 
is  of  importance  to  note  that  the  ordinary  antiseptics  do  not  act  more 
strongly  on  microbes  than  on  the  tissues  in  which  they  are  embedded. 
The  destruction  of  the  septic  organisms  in  a  wounded  surface  entails 
the  destruction  of  the  surrounding  cells  also.  Thus  disinfection  can 
only  be  carried  out  in  a  part  in  which  the  superficial  cells  are  not  of 
vital  importance  and  may  be  restored  by  new  growth.  It  is  therefore 
impossible  to  disinfect  the  tissues  of  the  body  as  a  whole,  because  a 
drug  circulating  in  the  blood  in  sufficient  quantity  to  destroy  the  bacteria 
in  the  body  would  be  equally  detrimental  to  the  organs  in  which  they 
are  embedded.  Unless  a  drug  has  a  specific  affinity  for  the  parasite,^ 
much  greater  than  that  for  the  tissues  of  the  host,  it  can  only  be  used 
where  the  parasite  can  be  overwhelmed  by  a  massive  dose,  and  this  at 
the  expense  of  the  neighboring  tissues.  In  spite  of  much  endeavor, 
no  chemical  substance  is  yet  known  which  possesses  this  specific  pre- 
dilection for  the  invading  microbes  of  most  diseases.  Certain  apparent 
exceptions  to  this  rule  will  be  discussed  later. 

The  antiseptics  and  disinfectants  act  upon  most  forms  of  living 
matter,  and  in  many  instances  their  effects  are  obviously  due  to  their 
possessing  powers  of  oxidizing  or  of  coagulating  proteins.  In  other 
instances  their  destructive  action  is.  not  so  open  to  explanation.  And 
the  amount  of  destruction  induced  varies  with  the  degree  to  which  the 
poison  penetrates  the  tissues  to  which  it  is  applied.  For  example, 
mercuric  chloride  diffuses  deeply  into  tissues  to  which  it  is  applied 
and  causes  wide  destruction,  while  the  oxidizing  disinfectants  lose  their 
efficacy  on  meeting  proteins  and  thus  affect  only  the  most  superficial 
cells.  If  microbes  were  confined  to  the  surface,  the  latter  would  be  suffi- 
cient for  their  destruction,  but  in  order  to  disinfect  a  wound  it  is  neces- 
sary to  penetrate  more  deeply  and  thus  efficient  disinfection  implies  a 
certain  amount  of  destruction  of  the  tissues  in  which  the  microbes  are 
harbored.  This  local  destruction  of  cells  and  nervous  structures  induces 
pain  and  irritation  and  all  efficient  disinfectants  are  irritants.  Their 
action  as  irritants  arises  from  the  same  qualities  as  their  disinfectant 
power,  namely,  from  their  general  toxicity  to  living  matter,  and  it  is 
impossible  to  dissociate  the  one  from  the  other  and  to  produce  non- 
irritant  effective  disinfectants. 

When  a  surface  has  been  poisoned  by  means  of  disinfectants,  it 
heals  less  quickly,  and  this  has  led  to  the  more  sparing  use  of  antiseptics 
and  to  the  development  of  the  aseptic  method,  in  which  organisms  are 
excluded  instead  of  being  admitted  and  then  destroyed. 

In  additi(Hi  to  their  local  effect,  many  of  the  antiseptic  and  disinfectant 
drugs  have  a  further  poisonous  action  when  they  are  absorbed  and 

*  A  drug  which  has  a  specific  affinity  for  a  parasite  as  compared  to  the  organs  of  the 
host  is  said  to  be  parasitotropic,  while  the  affinity  for  the  organs  in  general  is  called  its 
organotropic  tendency. 


126  SUBSTANCES  ACTING  LOCALLY 

circulate  in  the  blood,  and  this  had  led  to  a  further  limitation  of  their 
use.  This  general  action  does  not  necessarily  arise  from  the  qualities 
which  render  them  antiseptic,  and  may  be  avoided  by  care  in  the  choice 
of  the  drug  and  in  its  use. 

The  action  of  different  drugs  upon  the  microorganisms  varies  in 
nature  in  the  same  way  as  the  action  on  other  living  cells.  Some  ap- 
parently penetrate  into  the  interior  in  virtue  of  their  solubility  in  lipoids, 
and  this  penetration  is  facilitated  by  anything  which  decreases  their 
solubility  in  the  surrounding  medium.  Others  accumulate  on  the  surface 
of  the  organisms  by  adsorption,  so  that  the  microbe  is  surrounded  by  a 
dense  layer  of  disinfectant.  Yet  others  appear  to  enter  into  true  chemical 
combination  with  the  constituents  of  the  parasites.  Some  of  the  anti- 
septics (e.  f/.,  carbolic  acid)  enter  the  cell  by  simple  diffusion  and  do  not 
accumulate  in  its  interior  in  greater  concentration  than  in  the  solution 
surrounding  it.  Others  {e.  g.,  corrosive  sublimate)  tend  to  accumulate 
in  the  cell  and  on  its  surface  by  adsorption,  and  thus  are  withdrawn 
from  the  solution  if  a  sufficient  number  of  microbes  are  present. 

The  efficiency  of  any  disinfectant  naturally  depends  on  the  con- 
centration in  which  it  comes  in  contact  with  the  microbes  and  the  time 
during  which  it  remains  in  contact  with  them.  Thus  a  solution  of  mer- 
curic chloride  of  the  strength  of  1  in  3000  is  much  more  efficient  than 
one  of  1  in  10,000,  and  after  exposure  to  a  solution  for  five  minutes  far 
fewer  microbes  escape  than  after  exposure  for  two  minutes.  Another 
factor  is  the  temperature  at  which  the  microbes  are  exposed  to  the 
disinfectant,  for  it  is  found  that  when  the  latter  is  kept  at  about  30°  C. 
far  fewer  bacteria  escape  than  when  ordinary  room  temperature  prevails. 
Different  species  of  microbes  vary  in  their  resistance,  and  different 
cultures  of  the  same  microbe  and  even  different  individuals  of  the  same 
culture  exhibit  marked  variations  in  susceptibility.  The  effect  also 
often  varies  inversely  with  the  number  of  microbes  present,  because 
each  of  these  withdraws  a  certain  amount  of  the  disinfectant  and  thus 
reduces  the  general  concentration  of  the  solution.  And  other  proteins 
have  the  same  influence  as  the  microbes  themselves,  for  they  offer  the 
disinfectants  the  same  surface  for  adsorption  or  combine  with  some  of 
them  in  the  same  way  as  the  proteins  of  the  microbes.  Thus  a  con- 
centration which  is  sufficient  to  sterilize  water  infected  with  bacteria, 
may  have  little  or  no  effect  if  applied  to  a  sui)i)urating  wound,  because 
the  greater  part  of  the  disinfectant  is  taken  up  or  otherwise  rendered 
inactive  by  the  proteins  of  the  secretion,  leaving  only  a  low  concentration 
to  act  on  the  microorganisms.  Thus  Bechhold  has  shown  that  many 
substances  which  are  powerful  disinfectants  in  ordinary  fluids,  lose 
their  activity  in  protein  solutions,  owing  to  their  forming  combina- 
tions with  the  jiroteins,  so  that  though  they  are  not  dangerous  to  the 
host,  the>'  are  comparatively  innocuous  to  the  microbes  in  the  tissues; 
in  fact  they  act  on  proteins  and  not  specifically  on  microbes;  when 
tiie  proteins  are  present  in  small  amount,  as  in  an  cnnilsion  of  bacteria 
in  water,  these  disinfectants  are  active  enough,  but  when  the  bacteria 
are  distributed  among  the  proteins  in  an  infected  wound,  the  amount  of 


ANTISEI'TICS  AXD  DISIXFECTANTS  127 

the  disinfectant  that  falls  to  the  share  of  the  bacterial  proteins  is  too 
small  to  be  effective.  For  example,  a  disinfectant  which  prevented 
the  growth  of  diphtheria  germs  in  broth  when  added  in  the  proportion 
of  one  in  half  a  million,  had  no  action  on  the  germs  in  the  tissues  when  it 
was  present  in  the  proportion  of  one  in  five  thousand,  because  it  com- 
bined with  the  tissue  proteins  in  preference  to  those  of  the  bacilli. 

This  again  indicates  the  limitation  of  disinfectant  therapeutics, 
which  cannot  be  overcome  as  long  as  the  drugs  have  no  elective  affinity 
for  the  invading  organisms  but  act  equally  strongly  on  the  tissues  of  the 
higher  animals. 

If  a  poison  is  to  penetrate  into  the  interior  of  an  organism  in  quan- 
tity, it  must  be  as  soluble  in  the  protoplasm  as  in  the  fluid  in  which 
it  is  applied,  for  it  is  obvious  that  it  will  not  leave  a  medium  in  which 
it  is  readily  soluble  for  one  in  which  it  is  dissolved  with  difficulty. 
Accordingly,  it  is  found  that  fats  and  oils  in  which  the  members  of 
the  aromatic  series  are  very  soluble  are  not  suitable  as  media  for  their 
application,  for  the  poisons  remain  in  the  oily  menstruum  and  fail  to 
penetrate  the  microbes  in  which  they  are  less  soluble.  On  the  other 
hand,  the  addition  of  inorganic  salts  to  an  aqueous  solution  of  carbolic 
acid  often  increases  its  antiseptic  power,  because  the  poison  becomes 
less  soluble  in  the  water  and  shows  a  greater  tendency  to  escape  from 
it  into  the  interior  of  the  microbes. 

There  is  reason  to  believe  that  solutions  containing  several  disinfec- 
tants are  more  strongly  antiseptic  than  those  containing  an  equal 
percentage  of  the  individual  pure  bodies;  for  example,  a  mixture  of 
carbolic  acid  and  mercuric  perchloride,  is  more  efficient  than  a  much 
stronger  solution  of  either  alone.  This  appears  to  be  due  to  a  change  in 
the  solubilit}^  of  the  disinfectant,  at  any  rate  in  some  cases. 

Disinfectants  and  antiseptics  are  used  for  a  large  variety  of  purposes 
and  it  may  be  well  to  consider  the  principles  which  underlie  their  uses 
before  discussing  the  special  features  of  each  drug. 

1.  In  Surgery,  Lister  advised  that  not  only  infected  wounds  should  be 
treated  with  disinfectants  but  that  infection  "of  any  wound  should  be 
guarded  against  by  the  application  of  antiseptics  which  would  retard 
the  growth  of  microbes.  It  is  now  recognized,  however,  that  a  clean 
wound  requires  no  antiseptics  and  heals  more  quickly  if  they  are  avoided. 
And  disinfection  in  surgery  is  now  applied  only  to  tissues  already  the 
seat  of  infection,  and  to  objects  which  may  come  in  contact  with  a  clean 
wound.  Among  the  latter,  those  which  offer  the  greatest  difficulty 
are  the  skin  of  the  patient  and  of  the  operator,  and  a  large  number  of 
drugs  have  been  employed  to  disinfect  these  and  render  them  harmless. 
Among  the  disinfectants  more  commonly  used  to  disinfect  the  skin  or 
to  destroy  the  organisms  in  a  wound  already  infected,  are  the  carbolic 
acid  group,  mercuric  chloride,  the  oxidizing  disinfectant  group,  and 
iodine,  of  which  the  last  has  recently  been  the  most  popular.  The 
disinfectant  must  be  applied  in  solution  or  suspension  in  water,  and 
should  induce  as  little  irritation  as  is  compatible  with  its  fulfilling  its 
purpose.     This  is  of  special  importance  in  dealing  with  the  delicate. 


128  SUBSTANCES  ACTING  LOCALLY 

sensitive  mucous  membranes  such  as  the  eye,  which  cannot  be  subjected 
to  such  treatment  as  would  be  necessary  in  other  parts  of  the  body. 
A  danger  which  is  smaller  now  than  formerly  is  from  the  absorption 
of  the  disinfectant  giving  rise  to  general  poisoning.  This  arose  as  a 
general  rule  not  from  the  drug  applied  during  the  operation,  but  from 
its  too  lavish  use  in  the  subsequent  dressings.  But  cases  of  poisoning 
are  still  met  from  the  use  of  powerful  disinfectants  to  wash  out  large 
abscesses,  the  uterus,  or  other  organs. 

Instruments,  ligatures,  etc.,  are  generally  disinfected  by  heat,  but 
are  often  kept  in  dilute  solutions  of  carbolic  acid  or  other  disinfectant 
until  required. 

The  relative  disinfecting  power  of  the  drugs  used  in  surgery  has  been 
investigated  repeatedly  but  no  satisfactory  ratio  can  be  given  as  yet, 
because  it  is  impossible  to  imitate  the  conditions  in  a  septic  wound 
closely  enough  in  experimental  determinations.  And  estimations  of  the 
relative  power  in  destroying  organisms  in  water  or  in  gelatin  cultures 
depend  upon  a  variety  of  conditions,  such  as  the  number  of  organisms 
and  the  completeness  with  which  the  disinfectant  is  removed  before 
test  growths  are  made.  It  is  generally  held  that  among  the  disinfectants 
used  in  surgery  mercuric  perchloride  is  superior  to  the  carbolic  acid 
group,  and  that  both  of  these  penetrate  more  efficiently  than  the  oxidiz- 
ing disinfectants. 

2.  In  the  Treatment  of  Skin  Diseases,  a  number  of  disinfectants  have 
been  employed,  and  where  the  area  of  infection  is  small  it  may  be 
permissible  to  use  the  more  powerful  ones  if  necessary.  But  in  wide- 
spread disease  the  dangers  of  local  irritation  and  of  absorption  preclude 
all  except  the  least  noxious,  and  it  remains  a  question  how  far  these 
act  in  retarding  the  growth  of  an  infecting  organism,  and  how  far  their 
effects  may  be  due  to  their  causing  slight  irritation  and  improved 
nutrition.  Some  dermatologists  hold  the  view  that  these  mild  skin 
remedies  owe  much  of  their  value  to  their  reducing  proi)erties.  Among 
these  remedies  are  chrysarobin,  pyrogallol,  naphthol,  and  the  tar 
series. 

3.  To  Disinfect  the  Intestine. — Septic  processes  may  occur  either  in 
the  contents  of  the  intestine  or  in  its  walls,  the  former  affecting  the 
general  organism  only  by  the  production  of  poisonous  or  irritant  sub- 
stances which  may  be  absorbed,  while  in  the  latter  the  tissues  of  the  wall 
themselves  become  the  seat  of  active  disease.  It  is  possible  that  an 
admixture  of  a  disinfectant  with  the  contents  of  the  bowel  may  retard 
their  putrefaction,  and  this  method  of  treatment  has  been  largely  em- 
ployed. When  the  evidence  of  its  efficacy  is  examined,  the  results  prove 
to  be  disappointing;  the  amount  of  double  sulphates  or  of  indol  in  the 
urine  is  said  to  be  diminished,  and  the  number  of  microbes  in  the  fieces 
to  be  reduced  under  the  use  of  these  intestinal  antiseptics,  but  this 
is  no  longer  regarded  as  unequivocal  evidence  that  the  disintegration 
of  the  food  l)y  microbes  is  retarded;  and  in  addition  these  changes 
in  the  urine  and  the  fu'ces  have  not  been  confirmed  by  many  observers. 
There  is  some  rather  unconvincing  clinical  evidence  of  improvement 


^  ANTISEPTICS  AND  DISINFECTANTS  129 

under  this  treatment,  but  it  is  now  recognised  to  be  more  in  accord  with 
general  aseptic  procedure  to  remove  the  putrefying  contents  by  means 
of  a  purgati\-e,  than  to  attempt  to  render  them  sterile  in  the  bowel 
by  means  of  disinfectants. 

When  the  bowel  wall  itself  is  the  seat  of  infection  the  use  of  antiseptics 
and  disinfectants  is  still  less  supported  by  the  results.  And  it  seems  very 
unlikely  that  a  drug  powerful  enough  to  destroy  the  microbes  har- 
bored in  the  mucous  membrane  will  leave  the  latter  uninjured.  In 
typhoid  fever,  in  which  this  treatment  has  been  carefully  followed, 
the  number  of  typhoid  bacilli  in  the  stools  has  not  diminished  to  any 
noticeable  extent,  and  the  use  of  these  drugs  does  not  relieve  the 
symptoms  or  shorten  the  duration  of  the  disease. 

Any  drug  used  for  the  disinfection  of  the  intestine  must  not  be 
irritant,  nor  very  poisonous.  It  must  not  be  too  soluble,  since  other- 
wise it  may  be  absorbed  from  the  upper  part  of  the  bowel,  and  on  the 
other  hand  it  must  be  soluble  to  some  extent,  or  it  cannot  mix  very 
intimately  with  the  contents  of  the  intestine.  Carbolic  acid  is  scarcely 
fitted  for  this  purpose,  for  it  irritates  the  stomach  and  is  also  rapidly 
absorbed.  Some  of  the  cresols  have  been  recommended  of  late  years, 
and  the  naphthalin  preparations  have  also  enjoyed  some  reputation. 
Salol  and  its  congeners  have  the  advantage  of  being  almost  completely 
insoluble  and  harmless  in  the  stomach  and  of  being  dissolved  and 
rendered  active  by  the  intestinal  juices.  The  purgatives  are  the  most 
efficacious  treatment  and,  among  these,  the  mercurials  are  largely  used. 

4.  To  Destroy  Pathogenic  Germs  in  the  Tissues  After  Absorption. — It  is 
now  recognized  to  be  hopeless  to  attempt  to  find  a  single  body  which 
will  destroy  all  forms  of  bacteria  in  the  tissues,  while  leaving  the  host 
uninjured,  but  there  is  still  reason  to  believe  that  in  the  future  specific 
antiseptics  may  be  found  for  at  least  some  of  the  constitutional  diseases. 
Such  a  specific  action  is  seen  in  the  effects  of  quinine  on  the  organism 
of  malaria,  of  salicylates  in  rheumatic  fever,  of  mercury,  arsenic  and 
antimony  in  various  protozoal  infections,  and  of  emetine  in  amoebic 
dysentery,^  all  of  these  apparently  acting  more  strongly  on  the  cause  of 
the  disease  than  on  the  tissues  of  the  patient.  While  it  may  be  hoped 
that  the  antiseptic  treatment  of  internal  maladies  has  not  reached  its 
final  limit,  it  is  futile  to  attempt  to  disinfect  the  tissues  generally  with 
ordinary  agents,  which  are  much  too  poisonous. 

5.  In  the  Treatment  of  Septic  Genito-urinary  Diseases. — The  treatment 
of  general  infections  in  the  tissues  with  non-specific  disinfectants  is 
hopeless  for  the  reasons  given  above.  On  the  other  hand,  good  results 
are  obtained  in  infection  of  the  genito-urinary  tract  through  which 
many  of  the  antiseptics  are  eliminated  from  the  body.  In  the  course 
of  their  elimination  they  are  concentrated;  thus  a  quantity  of  dis- 
infectant which  is  inactive  when  distributed  through  the  protein-rich 

'  It  is  to  be  remarked  that  in  malaria,  syphilis,  dysentery,  and   trypanosomiasis,  in 
which  specifics  have  been  obtained,  the  disease  is  due  to  invasion  by  protozoa,  while  most 
of  the  infections  of  which  the  cause  is  known,  arise  from  bacteria,  and  these  appear  to 
be  much  less  susceptible  to  the  action  of  chemical  agents. 
9 


130  SUBSTANCES  ACTING  LOCALLY 

tissues  of  the  l)ody,  may  very  well  be  efficacious  when  it  is  dissolved  in 
the  comparatively  small  quantity  of  the  urine,  and  especially  since 
here  it  finds  no  protein  to  combine  with  except  that  of  the  tract  through 
which  it  passes.  On  the  other  hand,  in  their  passage  through  the  body 
the  antiseptics  are  generally  formed  into  combinations  which  are  less 
irritant  and  also  less  poisonous  to  the  microorganisms.  There  is,  how- 
ever, no  question  that  the  continual  washing  of  the  genito-urinary 
tract  with  the  antiseptics  in  the  course  of  their  excretion  reduces  the 
number  of  the  organisms  in  the  urine  and  relieves  septic  conditions. 
The  drugs  used  for  this  purpose  must  not  be  too  irritant  to  the  mucous 
membranes  of  the  alimentary  tract,  and  must  be  easily  absorbed  and 
not  dangerously  poisonous.  Many  of  the  aromatic  series,  such  as 
salicylates,  have  been  employed,  and  some  of  the  volatile  oils.  An 
important  advance  has  recently  been  made  in  urotropin,  which  is 
harmless  and  inactive  itself  but  frees  formaldehyde  in  acid  urine.  In 
addition  to  this  method  of  treatment,  antiseptics  and  disinfectants  may 
be  applied  by  injection  into  the  urethra  and  bladder  by  the  ordinary- 
surgical  procedure. 

6.  In  the  Treatment  of  Pulmonary  Infections. — Traces  of  some  of  the 
more  volatile  antiseptics  are  eliminated  in  the  breath,  and  this  has 
suggested  their  internal  use  to  destroy  microbes  in  the  lungs,  especially 
the  tubercle  bacillus.  It  may  be  stated,  however,  that  careful  observers 
are  united  in  the  belief  that  this  form  of  medication  is  entirely  useless. 
The  case  of  the  lungs  differs  entirely  from  that  of  the  kidney,  for  in  the 
former  there  is  no  concentration  of  the  disinfectant  in  the  organ,  but 
it  is  excreted  in  even  greater  dilution  than  that  in  which  it  circulates 
in  the  general  tissues.  In  addition  it  is  impossible  for  an  antiseptic  to 
reach  the  lungs  in  sufficient  concentration  to  incommode  the  resistant 
microbes  without  destroying  the  delicate  pulmonary  epithelium, 
unless  the  drug  has  a  specific  affinity  for  the  })arasites,  which  none  of 
the  general  antiseptics  has  proved  to  possess.  Antiseptic  remedies 
have  also  been  inhaled  in  vapor  or  spray,  and  have  been  injected  into 
the  trachea  or  even  into  the  lung  directly,  but  as  far  as  the  tubercle 
bacillus  is  concerned,  they  have  had  no  result  in  the  hands  of  more 
careful  observers.  In  cases  of  gangrene  of  the  lung,  fcrtid  bronchitis, 
etc.,  the  inhalations  relieve  the  patient  to  some  extent  and  certainly 
lessen  the  offensive  odor. 

7.  In  Infections  of  Other  Secretions  and  Organs,  the  use  of  antiseptics 
has  not  proved  successful.  In  the  bile,  thymol  and  urotroi)in  have 
been  found  after  administration  by  the  mouth,  and  the  latter  has 
been  shown  to  occur  in  the  cerebrospinal  fluid  and  in  many  other 
excretions,  but  it  is  to  be  noted  that  urotropin  is  in  itself  inactive  and 
is  disinfectant  only  through  its  liberation  of  formaldehyde,  which  has 
not  been  show  n  to  take  place  except  in  the  urine. 

8.  To  Disinfect  Rooms,  Furniture,  Clothing,  Excrementa,  the  strongest 
and  cheapest  drugs  which  are  available  are  emi)loyed.  It  is  quite 
futile  to  attempt  to  carry  out  such  disinfection  unless  with  concen- 
trations  which   would   be   iinniediateb    fatal   to  all   higher  organisms. 


ANTISEPTICS  AND  DISINFECTANTS  131 

For  rooms  and  furniture,  formaldehyde  or  sulphur  dioxide  are  best 
adapted  as  they  are  volatile  and  penetrate  fairly,  but  the  latter  bleaches 
all  dyed  material.  Clothes  are  best  disinfected  by  heat,  or  formaldehyde 
solution  may  be  employed.  Excrement  may  be  disinfected  by  chlorine 
or  lime;  crude  carbolic  acid  and  tar  are  less  certain,  and  the  oxidizing 
disinfectants  are  expensive  when  used  in  quantity. 

Bibliography. 

Gerhardt.    Ergebnisse  der  Physiol.,  hi,  p.  153. 

Mieczkowski.    Mit.  a.  d.  Grengebiet,  ix,  p.  405. 

Koch.     Mittheilung  aus  dem  Kaiserlich.  Gesundhcitsamt.,  i,  p.  234. 

Jalan  de  la  Croix.     Arch.  f.  exp    Path.  u.  Pharm.,  xiii,  p.  175. 

Sternberg.     Bull,  of  National  Board  of  Health,   1881. 

Kronig  u.  Paul.     Ztschr.  f.  Hygiene,  xxv,  p.  1. 

Spiro  u.  Bruns.    Arch.  f.  exp.  Path.  u.  Pharm.,  xli,  p.  353. 

Bechhold  n.  Ehrlich.     Ztschr.  f.  physiol.  Chem.,  xlvii,  p.  173;    Hi,  p.  177. 

Chick  and  Martin.     Journ.  of  Hygiene,  viii,  pp.  92,  655,  698. 

Verhoeff  and  Ellis.     Journ.  Amer.  Med.  Asso.,  1907,  i,  p.  2175. 

Cooper.    Bioehem.  Journ.,  ^^i,  p.  175. 

Kilster.    Arch.  f.  Hj-giene   1,  p.  364;   Zeitschr.  f.  Hyg.,  Ixxiii,  p.  205. 

Reichel.     Bioehem.  Zeitschr.,  xxii,  pp.   129,   175,  201. 

Paul,  Birstein  u.  Reuss.     Bioehem.  Zeitschr.,  xxv,  p.  367;    xxix,  pp.  202,  249. 

Harris.    Therap.  Research  Com.  Amer.  Med.  Asso.,  1912,  p.  151. 

Many  antiseptics  and  disinfectants  are  used  for  a  variety  of  purposes 
and  might  be  classed  under  several  of  these  headings.  The  following 
arrangement  is  therefore  an  arbitrary  one,  and  merely  points  to  the 
use  for  which  the  drug  has  been  considered  most  adapted. 

I.     Surgical  Antiseptics  and  Disinfectants. 
1.  Carbolic  Acid. 

Carbolic  acid,  or  phenol,  the  first  of  the  modern  antiseptics  to  be 
introduced,  acts  like  the  rest  of  the  simpler  benzol  compounds  as  a 
General  Protoplasm  Poison,  although  in  the  vertebrates  it  affects  the 
central  ner\ous  system  more  powerfully  than  the  other  tissues. 

Its  poisonous  effects  are  well  seen  when  it  is  applied  to  unicellular 
organisms,  such  as  the  protozoa.  Even  dilute  solutions  cause  immediate 
arrest  of  all  movements;  the  organism  assumes  a  spherical  shape 
and  loses  its  transparency,  and,  unless  the  solution  be  very  attenuated, 
dies  in  the  course  of  a  few  minutes.  Plant  cells  are  acted  on  the  same 
way,  and  the  individual  cells  of  more  highly  organized  animals,  such 
as  the  ciliated  cinthelium  of  the  air  passages  and  the  spermatozoa,  are 
killed  at  once  when  brought  in  contact  with  carbolic  acid.  There  is 
some  evidence,  however,  that  very  dilute  solutions  of  carbolic  acid, 
as  of  other  antiseptics,  tend  to  increase  the  activity  of  protoplasm,  for 
while  solutions  of  phenol,  such  as  are  used  as  Surgical  antiseptics,  are 
immediately  fatal  to  the  yeast  plant,  very  dilute  solutions  increase  its 
activity.  The  effect  of  carbolic  acid  on  protoplasm  has,  however,  been 
studied  chiefly  in  the  bacteria.  Its  antise])tic  power,  while  always 
considerable,  is  found  to  vary  greatly  with  the  species  of  microbe. 


132  SUBSTANCES  ACTING  LOCALLY 

Thus,  while  it  is  fairly  poisonous  to  the  ordinary  pyogenic  organisms, 
it  has  to  be  present  in  very  concentrated  form  to  destroy  the  more 
resistant  spores  of  anthrax,  and  like  other  antiseptics,  is  much  less 
poisonous  to  the  microbes  than  to  the  protozoa  and  other  simple  forms 
of  life.  The  development  and  reproduction  of  many  microorganisms 
has  been  found  to  be  much  delayed,  or  altogether  prevented,  as  long 
as  they  remained  in  a  solution  of  one  part  of  carbolic  acid  in  400-600 
parts  of  water,  but  in  order  to  kill  them  very  much  more  concentrated 
solutions  (5  per  cent.)  were  required,  and  Koch  found  that  the  spores 
of  the  anthrax  bacilli  were  destroyed  by  5  per  cent,  carbolic  solution 
only  after  they  had  remained  in  it  for  two  days. 

It  seems  to  vary  considerably  in  its  action  on  the  unorganized  fer- 
ments; thus  it  is  said  not  to  retard  appreciably  the  fermentations 
produced  by  emulsin,  diastase  and  my  rosin,  even  when  present  in 
the  solution  up  to  5  per  cent.,  while  pepsin,  ptyalin  and  the  rennet 
ferment  are  weakened  by  somewhat  smaller  quantities. 

Carbolic  acid  precipitates  Proteins  in  solution  and  also  in  the  cells. 
It  does  not  seem  to  enter  into  any  firm  combination  with  them,  for 
it  can  be  washed  out  of  the  precipitate  with  comparative  ease.  It 
results  from  this  that  carbolic  acid  penetrates  more  thoroughly  than 
the  metallic  antiseptics,  which  are  rendered  insoluble  by  the  albimiin 
they  meet,  and  whose  action  therefore  tends  to  remain  confined  to  the 
surface. 

This  coagulation  of  the  proteins  occurs  whenever  carbolic  acid  is 
brought  in  contact  with  the  tissues.  On  the  Skin  a  white,  opaque  scar 
is  formed  by  concentrated  phenol,  which  becomes  red  and  shining 
afterward  and  then  falls  off  in  a  few  days,  leaving  a  light  brown 
stain  which  may  remain  for  several  weeks.  Even  a  5  per  cent,  solution 
applied  to  the  fingers  produces  tingling  and  warmth,  which  is  often 
followed  by  opacity  and  shrinking  of  the  epidermis  and  a  sense  of 
ninnbness.  This  numbness  may  amount  to  almost  complete  annethesia 
if  more  concentrated  solutions  are  applied,  no  pain  being  felt  even 
when  the  skin  is  cut  through.  When  applied  for  some  time  and  pre- 
vented from  evaporating,  carbolic  acid  may  cause  extensive  dry  gangrene 
of  the  part,  from  its  penetrating  through  the  surface  layer  and  reaching 
the  deeper  tissues.  Applied  to  a  Wound  in  5  per  cent,  solution,  phenol 
induces  pain  and  irritation  followed  by  local  ana?sthesia,  and  a  white 
pellicle  of  coagulated  proteins  is  formed.  It  causes  irritation  and  necrosis 
of  the  Mucous  Membranes,  and  if  applied  in  sufficient  quantity  may 
lead  to  sloughing  and  acute  inllanunation.  This  local  elfect  may  prove 
fatal  from  shock  and  collapse  when  large  quantities  of  the  undiluted 
acid  are  swallowed,  the  effects  resembling  exactly  those  protluced 
by  other  corrosive  substances.  Carbolic  acid  is  rajiidly  absorbed  from 
the  stomach  and  bowel,  but  after  some  time  the  absorption  is  nnich 
slowed  owing  to  local  (■Jianges  in  the  v(>ssels  of  the  intestine". 

General  Action.  In  iikiii  dcliriuni  and  excitement  liaxc  been  obserxcd 
in  some  cases,  but  conxulsions  are  comparatixely  rarely  seen.  When 
large    quantities    are    taken,    inunediate    unconsciousness    may    result 


ANTISEPTICS  AND  DISINFECTANTS  133 

and  death  follow  within  a  few  minutes.  How  far  this  is  due  to  the  local 
corrosion,  and  how  far  the  direct  action  on  the  central  nervous  system  is 
involved,  cannot  be  determined.  In  more  gradual  poisoning,  depres- 
sion and  weakness,  headache,  nausea  and  vomiting  are  followed  by 
giddiness,  noises  in  the  ears,  pallor  and  collapse,  with  irregular  pulse 
and  respiration,  and  cold  perspiration;  fainting  and  unconsciousness 
then  lead  to  failure  of  the  breathing  and  death.  Fatal  poisoning  may 
arise  from  swallowing  a  concentrated  or  a  dilute  solution,  or  from 
absorption  from  wounds  and  abscesses.  It  has  also  occurred  in  man 
from  absorption  through  the  unbroken  skin. 

The  autopsy  sometimes  gives  no  special  indications  of  the  cause  of 
death,  save  the  local  corrosion  of  the  alimentary  canal.  Inflammation 
and  necrosis  of  the  intestine  is  said  to  have  been  observed  in  some 
cases  in  which  the  poison  was  absorbed  from  skin  wounds,  and  fatty 
degeneration  is  sometimes  induced  in  the  liver  and  the  renal  epithelium, 
but  is  not  constant. 

In  the  frog  carbolic  acid  first  causes  depression  and  loss  of  the  spon- 
taneous movements,  and  later  fibrillary  twitching  in  the  muscles, 
augmented  reflex  excitability  and  finally  tonic  convulsions.  These 
may  last  for  some  time  and  then  complete  paralysis  of  the  central 
nervous  system  supervenes,  while  the  heart  and  the  peripheral  nerves 
and  muscles  remain  active.  A  dilute  solution  of  carbolic  acid  applied 
directly  to  the  exposed  spinal  cord  paralyzes  the  sensory  elements 
immediately,  while  leaving  unaffected  the  motor  fibres  and  the  cells 
of  the  anterior  horn  (Baglioni). 

In  mammals  very  similar  symptoms  are  produced,  save  that  there 
is  often  no  noticeable  preliminary  stage  of  depression.  Some  weakness 
and  lethargy  may  be  present,  however,  and  is  followed  by  marked 
muscular  tremor,  which  resembles  the  shivering  produced  by  cold.  At 
intervals  this  is  interrupted  by  sudden  twitches  in  different  muscles, 
and  later  by  clonic  convulsions.  The  respiration  and  the  pulse  are  at 
first  accelerated,  but  afterward  are  slow,  irregular,  and  weak.  The 
movements  become  feeble  and  appear  at  longer  intervals,  the  respiration 
is  shallow  and  irregular,  and  the  animal  passes  into  a  condition  of 
collapse,  in  which,  however,  the  sensibility  to  pain  is  often  preserved. 
Eventually  death  occurs  from  asphyxia.  After  very  large  doses  the 
collapse  may  be  immediate,  no  convulsions  being  observed,  the  heart 
and  respiration  often  ceasing  simultaneously.  In  most  cases  salivation 
is  a  marked  symptom,  and  the  temperature  often  falls  far  below  the 
normal. 

Central  Nervous  System. — The  convulsions  in  the  frog  arise  from 
increased  irritability  of  the  spinal  cord,  especially  of  the  anterior  horn 
cells,  for  they  are  not  arrested  by  section  of  the  medulla  oblongata. 
In  mammals  the  sudden  contractions  of  isolated  muscles  appear  due 
to  a  similar  action  on  the  spinal  cord,  but  the  clonic  convulsions  and 
the  persistent  tremors  are  probably  of  cerebral  origin,  and  Berkholz 
found  the  cerebral  cortex  abnormally  irritable  after  carbolic  acid. 
The  rarity  of  convulsions  in  man  has  not  been  satisfactorily  explained. 


134  SUBSTANCES  ACTIXG  LOCALLY 

In  some  cases  the  course  of  the  intoxication  is  too  short,  the  large 
amount  of  poison  swallowed  inducing  immediate  collapse,  while  in 
others  their  absence  may  be  due  to  the  debility  of  the  patient  from 
disease;  but  in  a  considerable  number  of  cases  of  poisoning  in  which 
neither  of  these  conditions  was  present,  no  convulsions  were  observed. 
The  primary  stimulation  of  the  central  nervous  system  in  animals  is 
followed  by  depression  and  paralysis  if  large  doses  are  administered. 

The  acceleration  of  the  Respiration  and  of  the  Heart  seen  in  mammals 
has  been  supposed  to  be  an  indirect  result  of  the  increased  muscular 
movement  and  convulsions,  but  this  seems  to  be  incorrect,  for  the  heart 
is  found  to  be  accelerated  before  the  convulsive  movements  and  tremor 
appear,  and  the  frog's  heart  is  accelerated  in  cases  where  no  movements 
whatever  occur.  It  would  seem  probable  that  the  acceleration  of  the 
heart  is  due  to  direct  action  on  the  muscle  or  on  the  regulating  ner\es. 
The  subsequent  slowing  is  undoubtedly  due  to  muscular  action. 

The  acceleration  of  the  respiration  precedes  the  increased  move- 
ment also,  and  would  therefore  seem  to  be  due  to  action  on  the  medul- 
lary centre,  which  is  first  stimulated  and  later  paralyzed.  The  vaso- 
motor centre  is  said  by  Gies  to  be  depressed  at  once  by  the  injection 
of  carbolic  acid  into  the  blood,  but  it  may  be  questioned  whether  it 
too  is  not  first  excited  when  the  poison  is  absorbed  more  slowly.  It 
is  undoubtedly  depressed  in  the  later  stages  of  poisoning,  and  this, 
together  yviih  the  weakness  and  slowness  of  the  heart,  causes  a  fall  in 
the  blood-pressure  and  collapse. 

The  peripheral  Nerves  and  Muscles  do  not  seem  to  be  affected  in 
general  poisoning  in  mammals,  although  in  the  frog  their  irritability 
and  the  capacity  for  work  of  the  muscle  may  be  somewhat  reduced. 

On  the  direct  application  of  solutions  of  carbolic  acid  to  the  nerves 
or  muscles,  these  are  killed  at  once,  like  other  forms  of  living  matter; 
even  dilute  solutions  paralyze  the  nerve  fibrils  and  terminals  and  thus 
induce  local  anijesthesia. 

The  increased  Secretion  of  saliva,  perspiration  and  tears  which  is 
seen  in  poisoning  in  mammals  is  probably  of  central  origin,  and  may 
possibly  be  associated  with  the  nausea  and  vomiting. 

The  fall  in  Temperature  in  carbolic  acid  poisoning  seems,  for  the 
main  part,  to  be  due  to  the  collapse,  although  it  is  impossible  to  state 
how  far  this  may  be  aided  by  some  alteration  of  the  regulating  function, 
such  as  is  seen  in  the  closely  related  group  of  the  antipyretics. 

Carbolic  acid  added  to  the  defibrinated  Blood  leads  to  the  slow  for- 
mation of  methtemoglobin,  but  this  does  not  occur  in  the  living  animal. 
Occasionally  some  destruction  of  the  red-blood  cells  is  caused  in 
animals  through  the  injection  of  carbolic  acid  directly  into  the  blood- 
vessels, and  in  one  case  of  poisoning  in  man  luvmoglobin  was  detected 
in  the  urine,  indicating  that  some  of  the  red  cells  of  the  l>lood  had 
been  destroyed. 

Excretion. — Some  of  the  carbolic  acid  absorbed  is  oxidized  to  hydro- 
quinone  and  pynjcatechin,  and  these  and  also  the  unaltered  carbolic 
acid   are  excreted   in    the   urine    in    combination    with    sulphuric  and 


I 


ANTISEPTICS  AND  DISINFECTANTS  l.'^o 

glyciironic  acid.  The  hydroquinone  and  pyrocatechin  tend  to  become 
further  oxidized  to  colored  substances  and  the  urine  therefore  assumes 
a  dark,  (hisky-greeu  color  which  may  change  to  brown  or  even  black. 
This  change  may  occur  in  the  body,  and  the  urine  is  very  often  passed 
of  a  greenish-brown  color,  but  further  oxidation  takes  place  on  exposure 
to  the  air,  resulting  in  deeper  coloration  which  commences  at  the  surface 
of  the  fluid  and  gradually  extends  downward.  The  depth  of  the  shade 
depends  not  on  the  amount  of  phenol  sulphate  in  the  urine,  but  on  that 
of  the  dioxybenzols,  and  a  darker  urine  is  often  observed,  therefore, 
when  the  absorption  has  occurred  from  an  open  wound  (in  which  the 
conditions  are  especially  favorable  to  oxidation)  than  from  much  larger 
quantities  absorbed  from  the  alimentary  canal. 

The  presence  of  glycuronates  in  the  urine  may  lead  to  its  reducing 
Fehling's  solution,  and  thus  give  rise  to  the  suspicion  of  glycosuria. 
On  the  other  hand,  the  passage  of  these  bodies  through  the  kidney 
often  causes  some  irritation  and  albuminuria.  The  double  sulphates 
of  the  urine  are,  of  course,  much  increased,  and  the  inorganic  sulphates 
are  correspondingly  diminished. 

The  Chlorphenols,  in  which  chlorine  is  substituted  for  one  or  more  of  the 
hydrogen  atoms  of  carbolic  acid,  are  much  more  poisonous  to  microorganisms 
than  the  original  substance,  while  their  toxicity  in  mammals  is  not  increased 
in  the  same  ratio.  A  similar  intensifying  effect  is  seen  in  the  clilorine  sub- 
stitution products  of  the  narcotic  series,  e.  g.,  chloroform.  The  most  poisonous 
of  the  monoclilor-phenols  is  parachlorphenol.  Bromol  or  tribromphenol  has 
been  used  to  a  limited  extent  in  therapeutics  as  a  disinfectant  and  caustic. 

Preparations. 

AciDi-M  Carbolicum  (B.  p.),  Phexol  (U.  S.  P.),  carbohc  acid  or  phenol 
(CeHsOH)  forms  colorless,  deliquescent  crj'stals  when  recently  prepared,  but 
often  assumes  a  reddish  tinge  from  oxidation.  It  has  a  characteristic  odor 
and  is  intensely  corrosive.  It  is  soluble  in  about  20  parts  of  water,  but  be- 
comes hquid  when  10  parts  of  water  are  added  to  90  of  the  cr3^stals,  forming 
the  Acidum  Carbolicum  Liquefactum  (B.  P.),  Phenol  Liqiief actum  (U.  S.  P.). 
This  must  be  carefully  distinguished  from  the  ordinary  solution  of  carbolic 
acid,  wliich  contains  only  2  to  5  per  cent,  of  phenol,  while  the  liquefied  carbolic 
acid  contains  about  90  per  cent. 

Glyceritum  PhenoUs  (U.  S.  P.),  Glycerinum  Acidi  Carbolici  (B.  P.),  20  per 
cent,  of  carbolic  acid  in  glycerin.    0.3  c.c.  (5  mins.). 

Ungxientum  PhenoUs  (U.  S.  P.),  Unguentum  Acidi  Carbolici  (B.  P.),  3  per 
cent. 

Carbohc  acid  is  generally  used  in  2-5  per  cent,  solution.  A  crude,  impure 
form  may  be  employed  to  disinfect  stools,  latrines,  etc.  The  ointment  is  com- 
paratively seldom  prescribed,  as  it  is  found  more  irritant  than  many  other 
equally  powerful  antiseptics.  The  glycerite  may  be  used  as  a  very  weak  caustic. 
Solutions  of  carbohc  acid  in  oil  have  httle  or  no  antiseptic  action,  because  they 
fail  to  penetrate  into  the  microbes. 

Therapeutic  Uses. — Carbolic  acid  is  used  as  an  antiseptic  in  surgical 
operations  in  2-5  per  cent,  solution  in  water.  It  now  plays  a  much 
less  important  role  in  surgery  than  it  did  in  the  first  days  of  antisepsis; 
in  fact  in  many  clinics  it  is  now  employed  ouIn'  to  preserve  the  instru- 


136  SUBSTANCES  ACTING  LOCALLY 

ments  from  infection.  Its  irritant  action  and  the  danger  of  absorption 
have  also  rendered  it  unpopnlar  as  a  dressing  or  lotion  after  operations 
or  injuries,  where  there  is  any  large  absorbent  surface,  or  where  irrita- 
tion is  liable  to  be  injurious,  as  in  most  forms  of  skin  disease. 

It  is  still  used  as  a  disinfectant  in  septic  wounds,  though  greater 
reliance  is  now  placed  on  corrosive  sublimate.  Strong  carbolic  acid 
has  been  applied  to  disinfect  wounds,  its  poisonous  effects  being  avoided 
by  immediately  washing  it  off  with  alcohol. 

Harrington  has  recently  drawn  attention  to  the  danger  of  applying 
dilute  solutions  in  bandages  to  injured  fingers  and  hands;  he  found 
records  of  over  a  hundred  cases  in  which  this  had  led  to  gangrene, 
necessitating  amputation. 

Carbolic  acid  had  a  limited  use  as  a  caustic  in  the  form  of  the 
liquefied  preparation,  and  was  less  painful  than  most  other  caustics. 
It  has  also  been  employed  in  itching  skin  diseases,  but  is  inferior  to 
the  cocaine  series.  Internally,  it  was  at  one  time  advocated  as  an 
intestinal  disinfectant  and  as  a  remedy  in  constitutional  diseases,  but 
this  has  long  been  abandoned. 

Poisoning. — In  carbolic  acid  poisoning,  when  it  has  been  taken  by 
the  mouth,  the  first  treatment  is  the  removal  of  the  poison  by  the 
stomach  tube  and  the  thorough  lavage  of  the  stomach  with  water  to 
which  10  per  cent,  of  alcohol  may  be  added;  the  alcohol  dissolves  the 
poison  more  readily  than  water  and  thus  facilitates  its  removal,  but 
has  no  other  antidotal  action,  and  should  be  removed  from  the  stomach 
■as  completely  as  possible;  when  absorption  has  occurred  from  the  skin 
or  from  a  wound  the  dressing  should  be  removed  at  once.  The  com- 
bination of  phenol  with  sulphuric  acid  in  the  tissues  forms  a  compara- 
tively harmless  body,  and  Baumann  and  Preusse  therefore  suggested 
the  administration  of  sodium  sulphate  in  large  quantities.  It  is  found, 
however,  that  this  is  of  little  or  no  use,  because  the  })henol  does  not 
combine  sulphates  as  such  in  the  body,  but  with  organic  sulphur  com- 
pounds which  are  only  in  process  of  being  oxidized  to  sulphuric  acid. 
When  coma  and  collapse  set  in,  the  patient  is  to  be  sustained  by  the 
application  of  warmth  externally,  and  by  the  administration  of  such 
central  nervous  stimulants  as  caffeine  or  strychnine;  artificial  respiration 
may  eventually  be  used,  although  there  is  little  prospect  of  resuscitation 
if  the  intoxication  has  advanced  so  far.  The  corrosion  induced  by  car- 
bolic acid  locally  may  be  treated  by  washing  the  part  with  alcohol, 
wliich  dissolves  the  acid  readily. 

BiHLIOGRAPIIY. 

Iluseinann.     Arcli.  f.  cxp.  Path.  ii.  Pharm.,  iv,  p.  280. 

liaunxmn  and  liis  pupils.     Pflugcr's  Arcliiv,  xiii,  p.  285.     Zts.  f.  phys.  Choni.,  i,  p.  244, 
ii,  i)p.  27:i,  .SoO;    iii,  pp.  150,  177.    Arcli.  f.  Anat.  u.  Phys.,  1879,  p.  245. 
Bill.     AiiiLT.  Jour,  of  Med.  Sci.,  Ixiv,  p.  17. 

Salkowaky,  Iloppc-Seyhr,  Plnooc.     PfliiKer's  Archiv,  v,  pp.  335,  470,  538. 
Pruddcn.     Ani<T.  Jour,  of  Med.  Sci.,  Ixxxi,  p.  82. 
Tmthcr.     Arch.  f.  cxp.  Path.  u.  Phaini.,  xxxvi,  p.  197. 
Schiiiiedchcro.     Ibid.,  xiv,  p.  288. 
Turlschaninow.     Ibid.,  xxxiv,  p.  208. 


ANTISEPTICS  AND  DISINFECTANTS 


137 


Sollmann,  Brown,  Clarke.  Journ.  Amer.  Med.  Ass.,  March  17,  1906;  March  23,  1907. 
Journ.  of  Pharmacology,  i,  p.  409. 

Baglioni.  Arch.  f.  (Anat.  u.)  Phys.,  1900,  Supplem.,  p.  193.  Ztschr.  f.  allg.  Physiol., 
iii,  p.  313. 

Minervini.    Arch.  f.  kliii.  Chirurg.,  Ix,  p.  GS7. 

Harrington.    Atner.  Jour,  of  Med.  Sci.,  cxx,  p.  1. 

Schultzen,  Graebe,  Naunij^i.     Arch.  f.  Anat.  u.  Phys.  1867,  pp.  166,  349. 

Nencki.  Ibid.,  1870,  p.  399.  Zts.  f.  physiol.  Chem.,  iv,  p.  325.  Arch.  f.  exp.  Path, 
u.  Pharm.,  i,  p. .420;  xxx,  p.  300. 


2.  Cresols 

Of  late  years  the  cresols  or  cresylic  acids  (C6H4.CH3.OH)  have  been 
substituted  for  carboHc  acid  to  a  considerable  extent  in  surgery. 
There  are  three  isomeric  cresols  which  all  resemble  carbolic  acid  closely 
in  action,  and  which  present  only  minor  points  of  difference  from 
each  other.  Metacresol  is  said  to  be  less  poisonous  and  less  irritant 
than  carbolic  acid,  while  it  is  credited  with  a  more  powerful  antiseptic 
action;  orthocresol,  on  the  other  hand,  is  said  to  be  more  dangerous 
than  carbolic  acid,  and  paracresol  to  be  the  most  poisonous  of  all. 
But  the  differences  in  toxicity  between  the  cresols  are  too  small  to  be  of 
practical  importance,  and  their  germicidal  action  is  approximately  equal 
when  they  are  used  in  suspension  with  soaps,  as  is  usually  the  case. 

Many  cases  of  suicidal  poisoning  with  cresol  preparations  have 
occurred  and  have  presented  symptoms  similar  to  those  of  carbolic 
acid  poisoning — collapse  and  exliaustion  followed  by  coma  and  death; 
in  some  cases  marked  alterations  have  been  found  in  the  liver  along  with 
nephritis  and  haemolysis.  Much  of  the  cresol  absorbed  undergoes 
complete  oxidation  in  the  tissues,  but  about  one-third  of  that  ingested 
is  excreted  in  the  urine  in  combination  with  sulphuric  and  glycuronic 
acids. 

The  cresols  are  constituents  of  tars  and  other  crude  disinfectants. 
In  pure  form  they  are  only  slightly  soluble  in  water,  and  it  has  been  found 
necessary  to  form  them  into  emulsions  or  suspensions  for  surgical  use. 
A  large  number  of  these  cresol  preparations  are  available  and  differ 
chiefly  in  the  way  in  which  they  are  suspended  in  water  {creolin,  solveol, 
solutol,  lysol).  These  preparations  are  not  devoid  of  poisonous  properties 
as  is  often  stated;  on  the  contrary  they  are  little  if  at  all  less  dangerous 
than  carbolic  acid.  Their  germicidal  action  has  been  overrated  by  some 
authorities  and  has  been  denied  by  others.  On  the  whole  they  appear 
to  be  more  powerfully  antiseptic  than  carbolic  acid  when  they  are  used 
in  emulsion  form;  their  insolubility  in  water  facilitates  their  passage 
into  the  bacteria  in  which  they  are  more  soluble;  and  the  emulsion 
form  has  a  further  advantage  as  the  fluid  coming  in  contact  with  the 
bacteria  must  always  be  saturated  with  the  antiseptic.  Cresol  has  been 
given  as  an  intestinal  disinfectant,  but  has  not  proved  more  useful 
than  the  other  drugs  used  with  this  object. 

The  chlorcresols  are  said  to  be  more  strongly  germicidal  than  the  cresols 
themselves,  while  their  toxicity  is  not  increased  in  the  same  degree  or  may 
even  be  reduced;  a  suspension  of  chlorcresols  has  been  introduced  as  an  anti- 
septic, but  has  not  yet  been  widely  used. 


138  SUBSTANCES  ACTIXG  LOCALLY 


Prp:parations. 

Cresol  (U.  S.  P.,  B.  P.),  a  mixture  of  the  throe  cresols,  forms  a  colorless  or 
straw-colored  fluid  with  a  ])henol  odor.  Soluble  in  GO  jiarts  of  water.  Dose, 
0.05  c.c.  (1  mill.).;  B.  P.  1-3  mius. 

Liquor  CresoUs  Coinposilua  (U.  8.  P.),  Liquor  Cresol  Saponatus  (B.  P.),  Cresol 
50  per  cent,  .susjjendcd  in  water  b}^  means  of  soap,  is  used  diluted  to  about  5 
per  cent,  as  a  surgical  disinfectant. 

Bibliography. 

Seybold.     Ztschr.  f.  Hygiene,  xxix,  p.  377. 
Tollcns.    Arch.  f.  exp.  Path.  u.  Pharm.,  lii,  p.  220. 
Kochmann.     Arch,  internat.  de  Pharmacodyn.,  xiv,   p.  401. 
Blumcnthal.     Biochem.  Ztschr.,  i,  p.   134;    vii,  p.  39. 
Wandel.     Arch.  f.  exp.  Path.  u.  Pharm.,  hi,  p.  161. 
Schneider.    Arch.  f.  Hygiene,  Ixvii,  p.  1. 
Hale.    Hygienic  Laboratory,  Bulletin  No.  88,  1913. 
Siegfried  u.  Zimmerman.     Biochem.  Ztschr.,  xlvi,  p.  210. 

3.    Other  Aromatic  Surgical  Disinfectants. 

Many  other  members  of  the  benzine  or  aromatic  series  have  enjoyed 
a  more  or  less  transient  reputation  as  surgical  disinfectants  and  anti- 
septics. Thus  Thymol  (C6H3CH3C3H7OH),  obtained  from  oil  of  thyme, 
was  used  to  a  limited  extent  as  an  antiseptic  lotion  in  yV  per  cent, 
solution  and  also  as  a  mouth  wash  and  gargle,  but  in  this  strength  it 
is  only  feebly  active  and  it  is  too  insoluble  in  water  to  form  a  really 
effective  germicide.     It  is  used  as  an  anthelmintic  chiefly  (p.   120). 

Salicylic  acid  (C6H4OHCOOH)  and  sodiim  salicylate  (CeH^OHCOONa) 
were  at  one  time  used  as  antiseptic  washes  in  surgery,  and  indeed  prom- 
ised to  supplant  carbolic  acid  for  this  purpose  as  they  are  less  irritant 
and  less  poisonous.  The  acid  is  destructive  to  the  pyogenic  micro- 
organisms suspended  in  water  but  has  much  less  effect  than  carbolic 
acid  when  proteins  are  present,  and  its  use  has  been  abandoned  in 
practice  by  most  surgeons.  The  salicylates  are  used  almost  exclusively 
for  their  specific  action  in  acute  rheumatism. 

The  sidphocarbolates  (or  paraphenolsulpJwnates)  of  sodium  and  zinc  are  less 
poisonous  than  carbolic  acid,  as  the  sulphon  group  lessens  the  toxicit}-  in  the 
same  way  as  the  carbo.xyl  one,  but  they  are  at  the  same  time  very  nuich  weaker 
in  germicidal  i)ower.  They  hrf\'e  been  used  as  external  antiseptics,  and  the  sul- 
l)hocarbolate  of  sodium  has  been  administered  to  arrest  fermentation  in  the 
stomach  with  little  success.  Aseptol  or  sozolic  acid  is  a  33  per  cent,  solution  of 
ortho-phenol-sulphonic  acid  in  water,  but  very  often  contains  some  of  the  para- 
acid.  Of  the  three  phenol-sulphonic  acids,  the  ortho-  is  the  most  strongly 
antisei)tic  and  the  para-  the  least  useful. 

Sodii  Phcnohulphonua  (U.  S.  P.),  or  sodium  para-phenol-sulphonato  (CclL- 
OHS020Na,2IL.O),  forms  colorless,  transparent  prisms,  without  odor,  and 
with  a  saline  taste.    8olul)le  in  5  parts  of  water.     0.25  G.  (4  grs.). 

The  oxynaphioic  acids  (doHcOH  COOII)  jwssess  antisejitic  iMoperties, 
whic;h  are  said  to  be  somewhat  greater  than  those  of  carbolic  antl  salicj'lic 
acids,  but  they  are  less  .soluble  in  water,  while  the  sodium  salt  is  less  antiseptic. 
The  acids  are  irritant  and  produce  diarrlura  and  symptoms  similar  to  tho.sc  of 
salicj'lic  acid.  They  seem  to  be  at  least  as  poisonous  as  carbolic  .iciil,  and  have 
been  u.sed  ;is  external  anti.septics  only  to  a  very  limited  extent. 


ANTISEPTICS  AND  DISINFECTANTS 


139 


Turpentine  oil  and  many  of  the  other  volatile  oils  enjoy  a  reputation  as 
antiseptics  and  disinfectants,  and  have  been  applied  to  disinfect  the  skin  licfore 
opei'ations  and  for  similar  purposes. 

Chloroform  may  also  be  mentioned  as  a  disinfectant  in  use  in  the  laboialoiy 
though  it  has  never  been  adopted  in  surgical  operations. 

Alcohol  is  a  disinfectant  when  used  in  50-70  per  cent,  dilution,  and  has 
been  used  to  clean  and  disinfect  the  skin  and  hands  before  operation. 

4.  Mercuric  Perchloride. 

Soon  after  the  treatment  of  wounds  with  carbohc  acid  was  estab- 
lished, its  rival,  corrosive  sublimate,  was  introduced  as  a  more  powerful 
disinfectant.  There  is  no  question  that  the  claim  was  justified  and  that 
corrosive  sublimate  in  ordinary  surgical  practice  has  greater  germicidal 
and  antiseptic  powers  than  carbolic  acid.  At  the  same  time  bacteria 
must  be  exposed  for  a  longer  time  to  its  action  before  they  are  de- 
stroyed, and  it  has  a  more  injurious  effect  on  the  tissues  with  which 
it  comes  in  contact  and  is  more  poisonous  when  it  is  absorbed.  A 
certain  amount  of  mercury  remains  attached  to  the  proteins  of  the 
microbes  and  restrains  their  reproduction  even  when  it  does  not  act- 
ually kill  them ;  owing  to  this  fact  corrosive  sublimate  has  been  credited 
with  greater  disinfectant  power  than  it  merits,  for  it  is  found  that  on 
the  complete  removal  of  the  mercury  many  of  the  inactive  organisms 
recover;  in  practice  its  action  is  therefore  partly  disinfectant  and  partly 
antiseptic.  The  symptoms  of  mercuric  poisoning  and  the  general  action 
will  be  discussed  under  the  chapter  on  mercury  (see  Index). 

Mercuric  chloride  solution  (1  in  2000-4000)  is  used  extensively  in  sur- 
gery to  disinfect  the  hands,  skin  and  wounds,  but  is  very  irritant  to  the 
unbroken  skin  even  and  must  not  be  applied  to  more  delicate  tissues. 
It  corrodes  steel  and  this  precludes  its  use  to  preserve  instruments 
before  use.  It  is  sometimes  employed  in  the  form  of  a  soap  and  to 
impregnate  bandages,  cottonwool,  gauze,  catgut,  etc.,  but  it  renders  all 
of  these  irritant  and  corrosive  so  that  they  should  not  be  applied 
directly  to  wounded  surfaces.  It  differs  from  the  carbolic  acid  group  in 
preserving  its  disinfectant  powers  in  oils  and  fatty  vehicles,  in  wdiich  it 
is  only  slightly  soluble  and  which  it  therefore  leaves  readily  for  the 
fluids  of  the  microbes.  It  also  differs  from  carbolic  acid  in  the  fact 
that  the  presence  of  sodium  chloride  reduces  its  disinfectant  action 
because  it  lessens  the  amount  of  the  free  Hg  ion.  The  disinfectant 
action  of  corrosive  sublimate  is  much  diminished  by  the  presence  of 
protein  and  it  has  less  penetrating  power  than  carbolic  acid.  It  pre- 
cipitates the  protein  like  other  metallic  salts  and  has  a  further  specific 
toxic  action  on  living  tissue.  Various  other  mercurial  salts  have  been 
suggested  as  disinfectants,  for  example  the  cyanide  and  periodide;  but 
these  have  no  advantages  over  the  perchloride. 


5.    Other  Metallic  Disinfectants. 

The  salts  of  several  other  metals  have  been  used  as  disinfectants 
and  antiseptics.      Silver  nitrate  is  the  most  important  of    these  and 


140  SUBSTANCES  ACTING  LOCALLY 

plays  a  large  role  in  the  treatment  of  infections  of  the  mucous 
membranes,  especially  that  of  the  eye.  This  disinfectant  action  is 
accompanied  by  intense  irritation,  but  silver  nitrate  has  very  slight 
powers  of  penetration  because  it  is  rendered  insoluble  and  there- 
fore inactive  by  the  chlorides  of  the  tissues.  Silver  nitrate  is  used 
in  solutions  of  1  to  2  per  cent,  as  a  disinfectant  in  infectious  oph- 
thalmia, or  in  more  dilute  form  (1  in  200-400)  for  more  frequent 
application.  It  has  also  been  used  as  an  injection  in  gonorrhoeal  infec- 
tion of  the  urethra  in  the  strength  of  1  in  500-2000  and  in  various 
other  conditions.  General  poisoning  is  unknown  from  this  use  of  silver, 
but  its  intensely  caustic  action  and  the  limited  extent  to  which  it  pene- 
trates have  prevented  its  wider  employment.  This  irritant  action  of 
the  nitrate  has  led  to  the  introduction  of  various  other  salts  and  prepara- 
tions (see  Silver),  which  are  less  dissociated  in  solution  and  thus  are 
less  corrosive.  But  these  lose  their  disinfectant  power  in  the  same  ratio 
as  they  become  less  irritant,  for  the  tissue  destruction  arises  from  the 
same  factor  as  the  disinfectant  action,  the  free  silver  ion.  The  effects 
of  silver  after  absorption  will  be  discussed  later  (see  Index). 

f).    Oxidizing  Disinfectants. 
Peroxide  of  Hydrogen. 

Hydrogen  peroxide  or  dioxide  (H2O2)  tends  to  break  down  into 
water  and  oxygen  very  rapidly  in  the  presence  of  many  substances, 
which  in  themselves  may  be  either  oxidizing  or  reducing.  Among  the 
bodies  which  induce  this  decomposition  are  the  peroxidase  ferments, 
which  are  found  in  all  forms  of  living  matter,  and  the  peroxide  of 
hydrogen  is  therefore  decomposed  when  brought  in  contact  with  the 
tissues;  the  oxygen  thus  liberated  tends  to  oxidize  its  surroundings 
and  its  chief  effects  are  therefore  due  to  its  oxidizing  properties.  It 
is  generally  met  with  in  dilute  solution  in  w^ater,  and  in  this  form 
alone  is  used  in  medicine.  Brought  in  contact  with  the  skin,  peroxide 
of  hydrogen  solution  is  decomposed,  and  numerous  bubbles  of  oxygen 
are  formed,^  but  this  decomposition  proceeds  much  more  rapidly  when 
it  is  applied  to  denuded  surfaces  or  to  mucous  membranes.  The 
oxygen  is  formed  in  such  quantity  that  some  irritation  may  follow, 
and  thus  dogs  often  vomit  when  it  is  administered  in  quantity  by  the 
mouth.  When  it  is  injected  subcutaneously,  a  large  amount  of  oxygen 
is  formed  in  the  subcutaneous  tissues,  but  some  of  the  peroxide 
escapes  decomposition  and  is  absorbed  into  the  blood.  Here  the 
decomposition  proceeds  more  violently,  the  red-blood  cells  having  a 
strong  catalytic  action,  and  the  oxygen  set  free  may  cause  emboli  and 
lead  to  sudden  death.  The  formation  of  emboli  is  seen  most  frequently 
in  the  rabbit,  but  was  in  all  i)robability  the  cause  of  death  in  one  case 
of  fatal  poisoning  in  man,  in  which  a  solution  of  hydrogen  peroxide 

'  A  c()iK!(Mitrat('(l  solution  is  said  to  corrode  tho  skin,  lojivinp;  a  wliite  csnhar. 


ANTISEPTICS  AND  DISINFECTANTS  141 

had  been  used  to  wash  out  the  pleural  cavity.^  Emboli  are  not  formed 
in  the  dog  on  hypodermic  injection,  nor  in  either  dogs  or  rabbits  poisoned 
by  the  stomach — in  the  latter  case  probably  because  the  liquid  is  more 
slowly  absorbed  and  is  almost  entirely  decomposed  in  the  mucous 
membrane.  P^ven  in  the  blood  and  tissues  the  whole  of  the  peroxide 
is  not  decomposed,  for  several  observers  have  found  traces  of  it  excreted 
in  the  urine. 

The  catalysis  of  hydrogen  peroxide  occurs  in  the  lower  forms  of 
life  as  well  as  in  the  higher.  Thus  germinating  seeds,  yeasts,  infusoria 
and  the  microbes  all  free  oxygen  from  the  solution,  and  in  fact,  a 
rough  estimate  of  the  number  of  microbes  in  water  may  be  formed 
from  the  amount  of  oxygen  given  off  by  it  on  the  addition  of  the  per- 
oxide (Gottstein).  This  decomposition  is  fatal  to  most  of  these  lower 
forms,  from  the  nascent  oxygen,  and  peroxide  of  hydrogen  is  therefore 
a  powerful  disinfectant  in  water,  a  3  per  cent,  solution  proving  as  strongly 
bactericidal  as  a  1  per  mille  solution  of  corrosive  sublimate;  but  when 
the  microbes  are  contained  in  a  medium  with  much  organic  substance, 
as  in  wounds,  the  bactericidal  action  is  very  much  reduced.  This  appears 
to  be  due  to  the  too  rapid  decomposition  of  the  peroxide,  which  escapes 
as  bubbles  of  oxygen,  comparatively  little  oxidation  taking  place. 
This  may  be  exemplified  by  its  action  on  the  blood;  when  normal 
blood  in  a  test-tube  is  treated  with  peroxide,  it  froths  up  and  the  oxygen 
escapes,  leaving  the  blood  unaltered.  If,  however,  some  hydrocyanic 
acid  has  been  added  to  the  blood  sometime  previously  so  as  to  weaken 
the  ferment,  there  is  little  or  no  effervescence  and  the  haemoglobin  is 
changed  to  methsemoglobin  by  the  peroxide  remaining  and  freeing  its 
oxygen  more  slowly.  The  peroxide  therefore  oxidizes  most  powerfully 
when  it  is  slowly  decomposed,  while  the  rapid  action  of  the  ferments 
tends  to  dissipate  the  oxygen  in  the  molecular  form  which  has  com- 
paratively slight  oxidizing  and  disinfectant  powers. 

In  recent  years,  attention  has  been  drawn  to  other  bodies  analogous  to 
hydrogen  peroxide,  some  of  which  possess  powerful  microbicidal  properties. 
The  peroxide  is  represented  by  the  structural  formula  H — 0 — 0 — H  and  one  of 
the  hydrogens  may  be  replaced  by  benzoyl  or  acetyl,  forming  CeHsCO— 0— OH 
(benzo-peracid)  or  CH3CO— OOH  (aceto-peracid).  These  bodies  give  off  oxygen 
more  slowly  than  hydrogen  peroxide  and  surpass  it  in  germicidal  power;  in 
fact  they  are  as  powerful  disinfectants  as  corrosive  sublimate  in  favorable 
conditions.  Unfortunately  these  peracids  are  too  unstal)le  for  practical  use; 
and  the  organic  peroxides,  such  as  diacetyl  peroxide  (CH3CO— 0— 0— COCH3), 
which  form  the  peracids  in  water  have  not  proved  so  useful  clinically  as  the 
laboratorj^  results  seemed  to  promise. 

Preparations. 

Aqua  Hydrogenii  Dioxidi  (U.  S.  P.),  Liquor  Hydrogenii  Peroxidi  (B.  P.), 
solution  of  hydrogen  dioxide  or  jieroxide,  contains  'about  3  \)er  cent,  by  weight 
of  the  pure  dioxide.     Eacli  volume  of  this  solution  is  capable  of  setting  free 

'  In  several  other  instances  hemiplegia  has  been  ol^served,  apparently  from  embolism 
of  the  cerebral  arteries. 


142  SUBSTANCES  ACTING  LOCALLY 

10  volunios  of  oxygen  wlien  completely  decomposed.  Some  acid  is  added  to 
the  peroxide  solution  in  order  to  retard  its  decomposition,  but  it  gradually 
changes  when  kept,  so  that  only  freshly  prepared  solutions  are  of  full  strength. 
The  solution  is  colorless  and  odorless,  but  has  an  acid  taste  from  the  added 
acid,  and  the  oxygen  freed  in  the  mouth  gives  a  curious  sensation  and  forms  a 
froth. 

Therapeutic  Uses. — Hydrogen  dioxide  is  used  locally  as  a  disinfectant 
solution  in  suppuration,  diphtheria,  and  urethral  infection.  In  pus 
cavities  the  oxygen  is  freed  with  great  rapidity,  and  the  pus-corpuscles 
are  said  to  be  disintegrated.  The  catalysis  is  due  in  part  to  these 
corpuscles,  in  part  to  the  microbes,  and  the  extent  of  the  suppuration 
may  be  estimated  from  the  amount  of  effervescence.  Peroxide  solutions 
differ  from  most  other  disinfectants  in  the  short  duration  of  the  action, 
which  passes  off  as  soon  as  all  the  oxygen  is  liberated.  In  addition  to 
its  microbicidal  action  proper,  this  agent  loosens  and  destroys  masses 
of  infected  material  by  the  mechanical  effect  of  the  liberation  of  the 
gas,  and  the  wound  or  cavity  is  thus  cleaned  by  it  more  perfectly  than 
by  washing  with  ordinary  disinfectant  solutions.  INIost  surgeons  believe 
that  this  mechanical  action  is  of  more  importance  than  the  direct 
germicidal  effect.  The  solution  has  been  recommended  for  use  in  oph- 
thalmic practice,  and  for  this  purpose  may  be  diluted  one  half. 

Peroxide  has  been  used  to  destroy  the  bacteria  of  drinking  water  and 
10-15  c.c.  of  the  pharmacopoeial  solution  is  found  to  reduce  the  bacteria 
in  a  liter  of  water  more  than  100  times;  about  twice  as  much  is  required 
to  have  the  same  effect  in  milk. 

BlBLIOGR.\PHY. 

GxiUmann.    Virchow's  Archiv,  Ixxiii,  p.  23;    Ixxv,  p.  255 

Schwerin.    Ibid.,  Ixxiii,  p.  37. 

Altehoefer.     Centralbl.  f.  Bacteriol.,  viii,  1890,  p.  129. 

Gotislein.    Virchow's  Archiv,  exxxiii,  p.  295. 

Spitzer.     Pfliiger's  Archiv,  Ixvii,  p.  615. 

Honsell:    Beitrage  z.  klin.  Chir.,  xxvii,  p.  127. 

boew.    U.  S.  Depart,  of  Agriculture  Rep.,  No.  68. 

Wovy  and  Freer.    Journ.  of  Exp.  Med.,  vi.     (Peracids.) 

Other  Oxidizliu/  D  is  infect  cm  I  f<. 

Some  older  disinfectants  also  owe  their  jiowers  to  lii)eratcd  oxygen, 
and  among  these  that  most  largely  eini)l()yed  is  the  PrriiKUujnnate  of 
Pofds.siinn. 

^Vhcn  a  solution  of  this  salt  comes  in  contact  with  organic  matter, 
sucii  as  albumin,  the  j^ermanganate  at  once  parts  with  some  of  its 
oxygen,  whicli  attaches  itself  to  the  albumin.  Permanganate  is  thus 
poisonous  to  ])roto])lasin,  not  through  the  i)ri'scnc(>  of  the  whole  mole- 
cule, but  ill  coiisecjuencc  of  the  oxidation  of  the  ])roteins.  As  soon  as 
the  ])crui:iiigaiiatc  is  reduced,  it  of  course  loses  this  action,  so  that  the 
oxidizing  cll'cct  is  hniitetl  to  the  skin  and  the  surface  of  the  mucous 
membranes.  Concentrated  sohitions  irritate,  and  c\'cn  corrode  the 
skin,    and    induce   gastro-cntcritis    when    swallowed.        Pernuinganate 


ANTISEPTICS  AND  DISINFECTANTS 


143 


solutions  are  disinfectants  of  considera})le  power,  o\vin<^r  to  tlieir  oxi- 
dizing and  thus  destroying  bacteria.  They  fail  to  penetrate  deeply  in 
an  active  form,  and  this  renders  them  of  less  value  than  many  other 
disinfectants,  except  in  very  superficial  infection. 

Potassit  Pennmiganas  (U.  S.  P.,  B.  P.)  (KMn04)  forms  slender  crystals  of 
a  dark  purple  color  and  a  sweetish,  afterward  disagreeable  and  astringent 
taste,  soluble  in  sixteen  parts  of  water,  reduced  by  alcohol  and  other  organic 
bodies.     0.065  G.  (1  gr.);    B.  P.,  1-3  grs. 

The  permanganate  has  been  used  internally  in  amenorrhoea  and 
chlorosis. 

Externally  it  is  used  for  its  disinfectant  and  deodorant  action,  as 
an  application  to  gangrenous  ulcers,  cancerous  sores,  diphtheria,  and 
gonorrhoea.  In  dilute  solution  it  may  be  used  as  a  gargle  and  mouth 
wash  (J  per  cent.),  to  disinfect  the  hands  (1  per  cent.),  which  it  stains 
brown,  and  for  other  similar  purposes. 

It  has  recently  been  recommended  in  poisoning  with  phosphorus, 
prussic  acid,  morphine  and  other  alkaloids,  on  the  theory  that  these 
poisons  are  oxidized  by  it  in  the  stomach,  and  thus  rendered  harmless. 
For  this  purpose  it  is  given  in  one-third  per  cent,  solution.  But  per- 
manganate also  oxidizes  the  gastric  mucous  membrane,  and  it  has  not 
been  shown  that  it  attacks  morphine  in  preference  to  the  proteins; 
the  treatment  is  certainly  less  reliable  than  the  use  of  the  stomach  tube; 
permanganate  has  of  course  no  action  on  morphine  after  absorption. 
In  snakebite,  permanganate  has  been  used  to  wash  the  wound  and  also 
to  inject  around  it;  it  has  no  effect  upon  the  poison  already  absorbed. 

Condy's  Fluid  is  a  strong  solution  of  impure  permanganate,  which 
is  of  use  to  disinfect  and  deodorize  urinals  and  faeces,  but  must  be 
poured  on  them,  and  cannot  be  emplojed  to  disinfect  rooms. 

Some  of  the  caustics  owe  part  of  their  action  to  the  oxygen  liberated 
when  they  come  in  contact  with  organic  matter.  Thus  Chrovuc  Acid 
destroys  tissue  in  part  through  its  acidity  but  this  is  reinforced  by  its 
oxidizing  powers. 

Other  oxidizing  bodies  have  been  used  as  antiseptics  and  disinfectants. 
Thus  Calcium  Peroxide  or  Gorit  has  been  recommended  as  a  gastric 
and  intestinal  disinfectant  for  children  in  doses  of  0.2-0.6  G.  in  milk. 
Zinc  peroxide  and  magnesium  peroxide  have  also  been  suggested,  the 
former  for  external,  the  latter  for  internal  use. 

Similarly  the  Persidphates  of  potassium  and  sodium  (Na-jSoOg), 
persodine,  possess  strong  oxidizing  jjroperties  from  their  liberating 
oxygen  in  contact  with  organic  matter.  They  are  only  feebly  poisonous 
but  have  not  been  extensively  used  as  yet. 


7.  BoiiACic  Acid  and  Borax. 

Boracic  or  boric  acid  (B(OII),j)  is  a  very  weak  acid,  and  it  is  doubtful 
whether  the  hydrogen  ions  or  acidity  play  any  part  in  its  action,  or 
whether  the  whole  is  not  to  be  referred  to  the  rest  of  the  molecule. 
The  ordinary  sodium  compound,  borax,  Na2B407,  is  stated  by  some 


144  SUBSTANCES  ACTING  LOCALLY 

authors  to  be  equally  active,  but  is  alkaline  in  reaction,  so  that  the 
exact  relative  importance  of  the  two  ions  of  boric  acid  cannot  be  deter- 
mined. 

Action. — Boracic  acid  and  borax  are  only  feebly  toxic,  but  large 
quantities  taken  by  the  mouth  cause  gastric  and  intestinal  irritation, 
as  is  evidenced  by  vomiting  and  purging,  and  even  smaller  amounts 
are  said  to  act  as  mild  aperients  in  some  cases.  Not  infrequently 
repeated  small  doses  of  boric  acid  have  induced  albuminuria,  especially 
in  persons  predisposed  to  it.  Moderate  doses  are  without  effect  on  the 
metabolism,  but  larger  quantities  (5-10  G.  per  day  in  dogs)  increase 
the  nitrogen  excretion  in  the  urine.  A  dose  of  30-60  grs.  of  boric  acid 
is  found  to  increase  the  bulk  of  the  iveces  in  man  by  retarding  the 
absorption  of  the  proteins  and  fats.^  Both  borax  and  boracic  acid  are 
rapidly  absorbed  by  the  bowel,  and  do  not  aflfect  the  intestinal  putre- 
faction. 

Boracic  acid  has  been  widely  used  as  an  antiseptic  dressing,  and  a 
number  of  cases  of  serious  poisoning  have  been  recorded  from  its  ab- 
sorption. The  symptoms  arose  in  part  from  the  alimentary  canal, 
uneasiness  in  the  abdomen,  vomiting,  diarrhoea,  dryness  of  the  throat 
and  difficulty  in  swallowing;  sleeplessness,  great  muscular  weakness 
and  depression,  dimness  of  sight  and  headache  were  also  complained 
of,  and  in  severe  cases  collapse  and  death  followed.  The  prolonged 
use  of  boracic  acid,  internally  or  externally,  has  repeatedly  led  to 
falling  of  the  hair,  eczema,  and  psoriasis.  Papular  eruptions  and  local 
oedemas  and  swelling  of  the  skin  appear,  and  a  gray  line  on  the  gums, 
similar  to  that  seen  in  lead  poisoning,  is  stated  to  occur  along  with 
irritation  of  the  mouth. 

Boracic  acid  and  borax  are  excreted  in  the  urine,  in  which  they 
appear  within  a  few  minutes  after  ingestion;  over  half  the  quantity 
taken  is  excreted  within  twelve  hours,  but  afterward  the  elimination 
proceeds  more  slowly,  so  that  traces  may  be  found  in  the  urine  for 
five  days  or  more;  the  urine  becomes  alkaline  after  sufficient  amounts 
of  borax,  as  after  any  other  alkaline  preparation.  Boracic  acid  and 
its  sodium  salt  have  some  antiseptic  power,  for  in  2|  per  cent,  solution 
almost  all  forms  of  bacilli  stop  growing;  but  they  are  not  destroyed, 
even  the  delicate  anthrax  bacilli  being  found  capable  of  further  growth 
after  exposure  to  a  4  per  cent,  solution  for  twenty-four  hours.  Boracic 
acid  is  therefore  valueless  as  a  disinfectant,  but  has  been  used  as  an 
antiseptic  dressing;  it  has  the  advantage  over  many  other  antiseptics 
of  inducing  very  little  irritation  and  of  being  only  slightly  poisonous, 
but  experience  has  shown  that  it  cannot  be  used  with  impunity  in  very 
large  quantities. 

Acldum  Boricnm  (IJ.  S.  P.,  JJ.  P.),  Boric  or  Boracic  Acid  (II3BO3),  color- 
less crystals,  with  a  faintly  l)itl(M-  taste,  solulilc  to  al)out  4  percent,  in  water, 
more  so  in  alcoliol  and  ,<;;lycciiii.    ()..")  (5.  (7'.  '^ra.)]    B.  P.,  5-15  grs. 

'  Tlio  l)()(ly  wcifilit  oflcii  falls  iintlcr  borax  trfatnioiit,  and  this  has  been  attrilnited  to 
auKniciitcil  fat  (k-stniction  l)y  Host  and  Hiihiior,  who  state  that  a  corresponding  increase 
in  the  carbonic  acid  elimination  accompanies  it. 


ANTISEPTICS  AND  DISINFECTANTS  145 

Glyceritum  Boroglyccrini  (U.  S.  P.),  Ghjcennum  Acidi  Borici  (B.  P.).  Boro- 
glycerin  is  a  compound  formed  by  heating  boric  acid  in  glycerin,  and  the 
official  glyceritum  or  glycerinum  contains  this  dissolved  in  glycerin,  about  30 
parts  of  boric  acid  being  used  to  form  100  parts. 

Liquor  Antisepticus  (U.  S.  P.),  containing  2  per  cent,  of  boric  acid,  along 
with  benzoic  acid,  th3anol,  eucalyptol,  and  oils  of  peppermint,  wintergreen,  and 
thyme. 

Unguentum  Acidi  Borici  (B.  P.,  U.  S.  P.),  10  per  cent. 

Sodii  Boras  (U.  S.  P.),  Borax  Purificatus  (B.  P.),  Borax  (Na2B4O7+10H2O) 
forms  colorless  crystals  with  a  sweetish  alkaline  taste.  It  is  soluble  in  water  (25 
parts)  to  which  it  gives  an  alkaline  reaction.    0.5  G.  (7^  grs.);   B.  P.,  5-15  grs. 

Glycerinum  Boracis  (B.  P.)  (1  in  6). 

Boracic  acid  has  been  used  as  a  surgical  antiseptic  in  solution 
(4  per  cent.),  ointment,  or  lint,  and  the  solution  of  the  acid  or  of 
borax  is  also  used  as  a  wash  in  aphthae  and  other  forms  of  irritation  of 
the  mouth.  Boracic  acid  solution  has  been  given  internally  in  dilute 
watery  solution  as  a  genito-urinary  disinfectant,  has  also  been  injected 
into  the  bladder,  and  is  frequently  used  in  ophthalmic  surgery,  as 
being  less  irritant  to  the  e^'e  than  the  more  powerful  antiseptics."^  In 
internal  medicine  the  acid  and  the  salt  have  been  used  in  epilepsy, 
and  also  in  the  hope  of  dissolving  uric  acid  calculi,  but  have  not  been 
show-n  to  be  efficient  for  either  purpose.  Boracic  acid  and  borax  are 
sometimes  added  to  milk  or  other  food  as  preservatives,  and  it  has 
JDeen  much  discussed  whether  the  habitual  use  of  such  preserved  food 
is  likely  to  prove  deleterious  to  the  health.  The  general  result  of  the 
investigations  is  that,  while  no  preservative  should  be  added  to  food 
unless  it  is  absolutely  unavoidable,  boric  acid  is  less  liable  to  derange 
the  health  than  most  other  preservatives.  Foods  preserved  with 
boracic  acid  should  not  be  used  by  delicate  individuals  or  by  children, 
however,  and  the  quantity  of  the  acid  used  must  be  strictly  limited. 

Bibliography. 

Neumann.    Arch.  f.  exp.  Path.  u.  Pharm.,  xiv,  p.  149. 

Forster.    Arch.  f.  Hygiene,  ii,  p.  75. 

Rost  u.  Sonntag.    Arb.  a.  d.  Kais.  Gesundheitsamte,  xix,  p.  110. 

Heffter.     Ibid.,  xix,  p.  97. 

Chittenden  and  Gies.    Am.  Journ.  of  Phys.,  i,  p.  1. 

Wild.     Lancet,  1899,  i,  p.  23. 

Tunnicliffe  and  Rosenheim.     Journ.  of  Hygiene,  i,  p.  168. 

Vaughan  and  Veenboer.    Amer.  Medicine,  March  15,  1902. 

8.  Potassium  Chlorate. 

The  chlorate  of  potassium,  introduced  into  therapeutics  on  the  erro- 
neous theory  that  it  would  supply  oxygen  to  the  tissues,  has  been  used 
very  extensively  for  its  effects  in  certain  diseases  of  the  mouth.  It 
was  supposed  to  be  entirely  devoid  of  poisonous  properties,  but  was 
shown  by  Jacobi  to  give  rise  to  very  grave  and  even  fatal  symptoms 
in  some  instances.  But  the  conditions  which  determine  their  appear- 
ance are  not  universally  present,  for  very  often  large  quantities  have 
been  taken  with  impunity. 

10 


146  SUBSTANCES  ACTING  LOCALLY 

Symptoms. — The  chlorates  have  a  cool,  saline  taste,  which  persists 
for  a  long  time  owing  to  their  being  excreted  in  part  in  the  saliva. 
Concentrated  solutions  may  cause  nausea  and  vomiting  from  their 
local  salt-action  in  the  stomach,  and  their  absorption  is  often  followed 
by  considerable  diuresis  from  a  similar  action  in  the  kidney.  In  the 
great  majority  of  cases  no  further  effects  are  observed. 

In  some  individuals,  however,  symptoms  arise  from  a  single  large 
dose,  or  from  smaller  quantities  taken  repeatedly.  In  Acute  Chlorate 
Poisoning,  the  first  symptom  is  often  prolonged  and  violent  vomiting, 
with  pain  in  the  stomach  region;  diarrhoea  and  a  dark  cyanotic  color  of 
the  skin  and  mucous  membranes  follow,  the  respiration  is  at  first 
dyspno-ic  and  then  weak,  the  pulse  quick  and  feeble,  sometimes  irregular. 
The  patient  complains  of  headache,  giddiness  and  muscular  w^eakness, 
is  restless,  and  eventually  bcomes  comatose  before  death. 

In  Subacute  Poisoning,  vomiting  and  diarrhoea  are  also  observed, 
and  the  vomited  matter  often  contains  large  quantities  of  bile,  less 
often  blood.  There  may  be  complete  anuria  for  some  time,  or  the 
urine  is  scanty  and  at  first  dark  colored,  then  deep  reddish-brown; 
it  contains  haemoglobin,  methjemoglobin,  and  hsematin  in  solution. 
On  standing,  it  deposits  casts  of  brown  amorphous  particles,  which 
arise  from  the  destruction  of  the  red  cells  of  the  blood,  and  chlorates 
are  contained  in  it  in  considerable  quantity.  The  methsemoglobin 
may  disappear  from  the  urine  after  one  or  two  days,  but  the  casts 
remain  longer.  The  skin  is  often  icteric  in  color,  and  in  some  cases 
erythematous  eruptions  have  been  observed.  Headache,  muscular 
weakness  and  abdominal  pain  are  complained  of,  and  uraemic  symp- 
toms may  arise — delirium  and  convulsions,  or  confusion  and  coma. 
Death  has  followed  from  these  last  as  late  as  a  week  after  the  first 
symptoms  of  poisoning  were  observed,  but  in  several  cases  complete 
recovery  has  followed  even  the  gravest  symptoms. 

Action. — ^These  symptoms  arise  from  the  action  of  chlorates  on  the 
red  cells  of  the  blood  and  especially  on  the  haemoglobin.  When  chlorate 
solution  is  added  to  blood  in  a  test-tube  it  slowly  forms  metha^noglobin 
and  ha'Uiatin,  and  the  blood  assumes  a  chocolate  brown  color.  Later, 
the  red  cells  tend  to  become  laked  and  the  methivmoglobin  is  freed  in 
the  serum.  This  action  on  the  blood  is  generally  ascribed  to  the  oxidizing 
properties  of  the  chlorates,  for  other  oxidizing  agents  have  the  same 
effects;  some  oxicHzing  agents  induce  marked  luemoiysis  with  little 
methjemoglobin,  while  in  others  the  latter  feature  is  the  predominating 
one.  There  is,  however,  some  difficulty  in  explaining  the  chlorate  action 
by  oxidation,  for  these  salts  are  very  stable  and  have  practically  no 
oxidizing  action  at  body  temjierature. 

When  this  transformation  of  the  haemoglobin  takes  place  in  the 
vessels,  asphyxia  results  from  the  inability  of  the  blood  to  carry 
available  oxygen,  and  this  is  unquestionably  the  chief  cause  of  the 
symptoms  and  of  the  fatal  issue  in  the  most  acute  form  of  intoxication. 
When  a  c()nsi(leral)le  amount  of  hiemoglobin  is  transformed,  but  suffi- 
cient remains  to  continue  the  respiration  of  the  tissues,  the  subacute 


ANTISEPTICS  AND  DISINFECTANTS  147 

form  of  poisoning  results  from  the  haemolysis;  the  h;emoglobin  and  frag- 
ments of  the  corpuscles  obstruct  the  renal  tubules  with  masses  which 
may  appear  as  casts  in  the  urine,  or  may  cause  complete  suppression; 
the  fatalities  in  subacute  chlorate  poisoning  appear  to  be  the  result  of 
these  renal  changes.  Some  of  the  products  of  the  hiriemoglobin  are 
deposited  in  the  liver  and  spleen  and  often  cause  enlargement  of  these 
organs;  the  bile  pigment  is  increased  in  amount  and  the  bile  passes 
through  the  duct  with  difficulty  and  this  leads  to  the  absorption  of  bile 
and  jaundice. 

The  haemoglobin  of  most  animals  seems  equally  easily  transformed 
to  methaemoglobin  by  chlorates  when  it  is  dissolved  in  water,  but  the 
blood-corpuscles  of  the  rabbit  and  guinea-pig  resist  their  action  much 
more  than  do  those  of  the  dog  and  of  man.  Apparently  the  corpuscles 
of  the  rabbit  are  less  permeable  by  chlorate  than  those  of  the  carnivora 
and  man  and  the  true  chlorate  symptoms  are  rarely  elicited  in  rabbits, 
while  dogs  and  cats  show  the  same  effects  as  man. 

Chlorate  has  little  or  no  direct  eflFect  on  the  central  nervous  system 
or  the  circulation,  though  these  are  secondarily  affected  by  the  asphyxia 
and  renal  changes. 

Very  little  chlorate  is  reduced  in  the  blood  and  tissues,  for  90-96  per 
cent,  of  the  amount  administered  has  been  recovered  from  the  urine. 
Small  quantities  appear  also  in  the  saliva  and  in  other  secretions, 
such  as  the  perspiration,  milk,  tears,  and  nasal  mucus,  and  some  has 
been  found  to  pass  from  the  mother  to  the  foetus  in  vfero. 

Chlorates  hardly  retard  the  growth  of  bacteria  in  cultures  more  than 
other  indifferent  salts,  and  no  adequate  explanation  has  been  offered 
for  their  use  in  infections  of  the  mouth  and  throat. 

The  Bromates  and  lodates  have  been  much  more  seldom  the  subject  of 
investigation  than  the  clilorates,  and  are  not  used  in  therapeutics.  The  iodates 
are  more  poisonous  than  the  bromates  and  these  again  than  the  chlorates;  the 
iodates  destro^^  the  red  cells  more  rapidlj^  but  form  less  methiiemoglobin  than 
the  chlorates  in  test-tube  experiments^  lodates  induce  fatty  degeneration  of 
the  liver  and  congestion  and  extravasation  in  the  alimentary  tract.  Some 
iodide  is  formed  from  them  in  the  liody. 

The  action  of  the  Perchlorates  has  been  examined  by  Kerry  and  Rost.  In 
the  frog  the  perchlorate  of  sodium  (NaC104)  induces  fibrillary  twitching  and 
clonic  contractions  of  the  muscles;  the  contraction  of  the  iliuscle  is  prolonged 
in  the  same  way  as  bj^  veratrine,  and  rigor  eventually  follows  as  in  caffeine 
poisoning.  The  reflex  excitability  is  increased  and  the  heart  is  slow  and  irregu- 
lar. The  effects  of  the  perchlorate  on  mammals  differ  considerably  in  different 
species;  in  the  rat,  mouse,  and  guinea-pig  the  reflex  excitability  is  enormously 
increased  and  tetanic  comailsions  may  arise  from  this  action;  in  the  cat  a 
certain  stiffness,  muscular  paresis  and  tremor  can  be  made  out  after  the  injec- 
tion of  large  cjuantities  of  perclilorate,  but  these  animals  as  well  as  the  rabbit 
and  dog  are  not  killed  by  even  very  large  quantities. 

PoTAssii  Chloras  (U.  S.  p.,  B.  p.),  (KCIO3),  0.25  G.  (4  grs.) ;   B.  P.,  5-1.5  grs. 

Trochisci  Potassii  Chloratis  (U.  S.  P.)  contain  0.15  G.  (0.2  G.,  B.  P.) 
■  chlorate  of  potassium  in  each  lozenge. 

The  chlorates  are  colorless  prismatic  crystals  with  a  saline  taste,  and  are 
given  in  solution  or  in  lozenges  when  used  internally.     The  dry  salts  form 


148  SUBSTANCES  ACTING  LOCALLY 

exi)losivc  mixtures  with  organic  or  otlier  reducing  sul)stance.s,  and  such  mix- 
tures are  tlierefore  to  be  kept  cool,  and  ought  not  to  be  ground  together,  as 
heat  and  pressure  are  hable  to  cause  explosions. 

Therapeutic  Uses. — The  clilorate  of  potassium  is  used  chiefly  as  a 
mouth  wash  and  gargle  in  irritable  conditions  of  the  mouth  and  throat, 
such  as  aphthse,  and  in  the  tenderness  and  ulceration  of  the  gums  and 
mouth  induced  by  the  prolonged  use  of  mercury.  It  may  also  be  given 
as  a  projjhylactic  to  lessen  stomatitis  when  mercury  is  being  prescribed. 
In  catarrh  of  the  throat  it  is  often  used  with  apparently  good  effects. 
It  is  rarely  employed  in  diphtheria  now. 

It  is  used  in  2-4  per  cent,  solution,  or  the  official  lozenge  may  be 
prescribed.  In  children  a  somewhat  stronger  solution  with  syrup  or 
honey  may  be  used  to  l)rush  out  the  mouth,  but  care  should  be  taken 
that  none  is  swallowed.  The  local  action  of  the  chlorates  has  not  been 
explained,  and  it  may  be  due  to  the  salt-action  in  part,  though  not 
wholly.  It  has  been  suggested  that  they  are  oxidizing  disinfectants, 
but  there  is  no  reason  to  suppose  that  they  are  changed  here  any 
more  than  in  the  tissues  in  general.  It  is  not  impossible  that  equally 
satisfactory  results  might  be  obtained  by  the  use  of  the  chlorides  or 
nitrates.  Chlorate  of  potassium  has  been  given  internally  in  cases  of 
diphtheria  and  in  some  diseases  of  the  mouth,  but  it  does  not  seem  to 
have  any  therapeutic  value  unless  when  ai)plied  locally.  Some  benefit 
may  arise  from  its  contact  with  the  mouth  and  throat  in  the  j)rocess 
of  swallowing  and  from  its  excretion  in  the  saliva.  In  addition  the 
internal  administration  of  the  chlorate  is  liable  to  induce  dangerous 
poisoning. 

Poisoning. — The  fatal  dose  of  chlorate  varies  extremely,  as  little  as 
1  G.  (15  grs.)  having  proved  fatal  in  a  child,  while  40-50  G.  (10-12 
drs.)  have  been  swallowed  by  adults  without  marked  symptoms. 
Chlorate  poisoning  is  now  very  rare;  it  is  said  to  be  more  liable  to 
occur  in  nephritis  than  in  normal  persons.  As  a  general  rule  symp- 
toms appear  only  two  to  three  hours  after  the  drug  has  l)een  taken, 
and  the  treatment  is  purely  symptomatic — central  nervous  stinuilants, 
ice  for  vomiting  etc.;  alkalies  may  be  given  to  lessen  the  formation 
of  methicmoglobin  and  diuretics  and  large  amounts  of  fluid  to  flush 
out  the  kidneys. 

Bibliography. 

Marchand.  Virchow's  Archiv,  Ix.wii,  p.  455.  Arch.  f.  Lxp  Path  ii  Phariii..  xxii.  p. 
201;    xxiii,  pp.  273  and  347. 

Mering.     Das  chlorsauic  KaU,  1S!S5,  Ik'iliii. 

Stokcin.     Arch.  f.  cxp.  Path.  u.  Pharni.,  xxi,  p.  109. 

Cahn.     Ibid.,  xxiv,  p.  180. 

Lewin  u.  Posner.     Centralljl.  f.  d.  incd.  \\'i.ssi'iiscli.,  1SS7,  p.  354. 

Diltrich.     Arcli.  f.  (!Xi).  Path.  u.  Pharm.,  xxix,  p.  247. 

liinz.     Il)id.,  X,  j).  153;    xxxi\-,  p.  1S5. 

Fctlck.      Pnimoi's  Aicliiv,   xlv,   p.  .301. 

Dre.icr.     Arch.  f.  fX|).  Path.  ii.  PhaiTii.,  xxxiv,  p.  201.     (lodatcs    Kioiiiatc.-^.) 

Kerry  u.   Host.      Ibid.,   xxxix.   \>.    141.      (Pcrchloratcs.) 

Malhcirx.     Aincr.  .louiii.  of  Pliysiol.,  xi,  p.  2.37. 

Cuiikny.     .\ich.  f.  cxp.  Path.,  Schniiodelicrg's  Fcstschr.,  p.  12(j. 


ANTISEPTICS  AND  DISINFECTANTS  149 


9.    Iodine. 

Iodine  lias  recently  been  used  largely  to  disinfect  the  skin  before 
operation,  as  it  is  found  to  penetrate  readily  into  the  pores  and  has  a 
very  powerful  germicidal  action.  Its  irritant  effects  preclude  its  more 
general  use.  It  is  generally  employed  in  the  strength  of  2^-5  per  cent, 
in  10  per  cent,  potassium  iodide  solution  or  in  alcohol,  and  is  painted 
on  the  site  of  operation  a  few  minutes  before  the  incision  is  made. 


10.  Iodoform. 

A  number  of  iodine  compounds  have  been  introduced  into  thera- 
peutics as  applications  to  wounded  surfaces.  The  most  widely  known 
of  these  is  Iodoform  (CHI3),  which  corresponds  in  its  chemical  structure 
to  chloroform,  and  has  been  used  very  extensively  in  surgery ;  it  formerly 
gave  rise  to  poisoning  repeatedly. 

Symptoms. — The  symptoms  of  iodoform  intoxication  in  man  gen- 
erally set  in  with  anxiety,  general  depression  and  discomfort.  The 
patient  becomes  sleepless  and  restless,  complains  of  giddiness  and 
headache  and  often  of  the  taste  and  odor  of  iodoform  in  the  mouth 
and  nose.  The  pulse  is  generally  greatly  accelerated,  and  a  rise  of 
temperature  is  said  to  have  occurred  in  some  cases  in  which  no  septic 
poisoning  could  be  found  to  account  for  it.  The  depression  deepens 
into  true  melancholia  accompanied  by  hallucinations,  the  patient  often 
suffering  from  the  illusion  of  persecution,  which  may  induce  him  to 
attempt  suicide.  As  a  general  rule  this  melancholia  is  followed  by 
attacks  of  violent  delirium  and  mania,  lasting  for  hours  or  days,  and 
in  fatal  cases,  by  collapse  and  death.  In  other  cases  the  condition  has 
passed  into  permanent  insanity  and  dementia.  A  rarer  result  of  the 
absorption  of  iodoform  is  deep  sleep  passing  into  stupor  and  collapse 
without  any  symptoms  of  cerebral  excitement. 

In  milder  cases  of  poisoning  the  patient  suffers  only  from  the 
unpleasant  taste  and  odor,  from  headache  and  not  infrequently  from 
nausea  and  vomiting. 

In  the  dog  and  cat  iodoform  generally  causes  deep  sleep  and  stupor, 
with  lessened  excitability  of  the  spinal  cord  and  of  the  motor  areas  of 
the  brain;  but  after  large  doses  excitement  and  convulsions  of  clonic 
and  tonic  types  have  been  observed.  In  the  frog  it  paralyzes  the  central 
nervous  system  and  the  heart  without  eliciting  any  symptoms  of  excite- 
ment. No  narcosis  is  observed  in  the  rabbit  even  after  fatal  doses. 
After  prolonged  administration  albuminuria  is  often  observed  in  animals, 
and  the  iodine  of  the  thyroid  has  been  found  to  be  increased  by  iodo- 
form, as  by  other  bodies  which  free  iodine  in  the  tissues. 

After  fatal  iodoform  poisoning  in  man  and  animals,  the  liver,  kidney, 
heart  and  muscles  are  generally  found  to  have  undergone  fatty  degenera- 
tion. In  addition,  irritation  of  the  gastric  and  intestinal  mucous  mem- 
brane has  been  observed,  and  the  epithelial  cells  are  often  degenerated. 


150  SUBSTANCES'  ACTING  LOCALLY 

Ecchymoses  occur  beneath  the  endocardium,  in  the  kidney  and  else- 
whore,  and  conf:;estion  of  the  meninges  is  described. 

Absorption  and  Excretion. — ^lodoform  is  readily  decomposed  in  the 
presence  of  alkaline  fluids  and  in  protein  solutions,  and  some  decom- 
position undoubtedly  takes  i)lace  in  wounds;  the  iodine  liberated  com- 
bines with  the  alkalies  of  the  fluids  to  form  iodides,  for  these  have 
been  shown  to  be  present,  and  iodalbuminates  are  presumably  formed 
in  the  same  way  as  by  free  iodine.  Some  of  the  iodoform  is  perhaps 
absorbed  unchanged.  After  iodoform  absorption,  iodine  has  been 
shown  to  be  present  in  the  saliva,  perspiration  and  bronchial  secretion, 
as  after  the  ingestion  of  iodine  or  iodides;  but  it  is  chiefly  excreted  in 
the  urine  in  the  form  of  iodides  and  partly  in  organic  combination. 
The  tissues  apparently  retain  it  very  tenaciously,  for  iodides  have  been 
found  in  the  urine  for  more  than  a  month  after  the  administration  of 
iodoform. 

In  considering  the  symptoms  of  iodoform  intoxication,  it  must  be 
recognized,  therefore,  that  a  very  complex  condition  is  present.  Some 
iodoform  may  circulate  in  the  blood  unchanged  and  give  rise  to  the 
cerebral  symptoms.  Other  symptoms  are  due  to  the  presence  of 
iodine  and  iodides  in  the  blood  and  tissues.  Lastly,  the  acceleration 
of  the  heart  and  some  other  symptoms  are  due  to  abnormal  activity 
of  the  thyroid  secretory  cells.  It  is  possible  that  the  cerebral  symp- 
toms may  arise  from  the  thyroid  gland  through  the  action  of  iodoform 
on  it,  but  this  has  not  been  demonstrated. 

Iodoform  has  no  marked  Local  Action  on  the  skin  or  mucous  mem- 
branes. Some  persons  have  a  special  idiosyncrasy  for  it  which  betrays 
itself  in  an  eruption  developed  in  the  skin  near  where  iodoform 
has  been  applied;  Bloch  states  that  a  skin  graft  from  these  persons 
implanted  in  a  normal  individual  continues  to  show  this  reaction,  but 
believes  that  the  idiosyncrasy  is  not  limited  to  iodoform  but  extends  to 
many  other  methyl  compounds.  It  seems  to  have  some  anaesthetic 
action,  when  applied  in  large  quantity  to  wounded  surfaces.  Iodoform 
was  at  first  applied  to  wounds  in  the  belief  that  its  Antiseptic  properties 
were  equal  to  or  even  exceeded  those  of  carbolic  acid.  But  cultures  of 
bacteria  are  not  prevented  from  developing  by  the  addition  of  iodoform. 
It  has  therefore  been  suggested  that  while  iodoform  in  itself  possesses 
no  antiseptic  virtues,  the  iodine  formed  from  it  in  the  wound  may 
retard  the  growth  of  septic  germs;  but  microbes  drawn  from  wounils 
under  iodoform  treatment  are  not  retarded  or  weakened  in  their 
development.  Some  of  the  advocates  of  the  iodoform  treatment, 
therefore  suppose  that  it  diminishes  the  secretion  of  the  wounded  sur- 
face and  thus  affords  a  less  suitable  medium  for  the  growth  of  the 
germs;  in  this  relation  it  may  be  mentioned  that  Binz  found  the 
emigration  of  the  leucocytes  from  the  bloodvessels  hindered  by  the  local 
ai)plication  of  iodoform.  Finally  iodoform  may  retard  the  growth  of 
microbes  to  some  extent  by  forming  a  crust  over  the  wounded  surface, 
and  nu-chanicaily  preventing  them  from  penetrating  to  it. 

The  intensely  disagreeable  odor  of  iodoform  and  its  toxicity  have 


ANTISEPTICS  AND  DISINFECTANTS  151 

lied  to  the  introduction  of  numerous  substitutes.  None  of  these  seem 
to  be  very  poisonous,  and  in  most  of  them  the  iodine  of  tlie  molecule 

ps  not  hberated  in  the  wound  or  tissues.  It  is  of  course  impossible  to 
state  how  far  they  are  capable  of  replacing  iodoform,  as  long  as  their 
gxact  action  in  wounds  is  unknown. 

The  first  of  these  substitutes  was  iodol  or  tetraiodpyrrol  (C4I4NH),  which 
las  no  odor  or  taste,  is  insoluble  in  water,  but  is  absorbed  from  mucous  sur- 
faces and  from  wounds.  It  is  decomposed  in  the  tissues,  and  leads  to  the  ex- 
cretion of  iodides  in  the  urine,  and  in  very  large  doses  gives  rise  to  symptoms 
animals  resembling  those  produced  by  iodoforai.  Others  are  aristol  or 
hthymol-diiodide  (CcH2CH3C3H70I)2,  and  the  potassium,  sodium,  mercury, 
md  zinc  salts  of  soziodolic  acid  (C6H2I2HOSO2OH).  Iodine  comj^ounds  of 
jhenol-phthalein  are  known  by  the  trade  names  of  nosophen,  mitinosine,  and 
fudoxine.  Triiodocresol  is  known  as  losophan,  while  europhen  is  a  more  complete 
[jombination  of  cresol  and  iodine;  loretin  and  vioform  are  derivatives  of  quino- 
Jline  containing  iodine.  (See  also  under  Bismuth  and  Alum.)  These  later  "sub- 
stitutes" for  iodoform  differ  entirely  from  it  and  from  iodol  in  the  fact  that  iodine 
is  not  liberated  by  the  tissues;  what  value  they  possess  is  probably  due  to  their 
acting  as  absorbent  powders,  and  precipitated  chalk  would  presumably  be  as 
efficient. 

lodoformum  (U.  S.  P.,  B.  P.),  iodoform  (CHI3),  forms  small,  lemon-colored 
crystals,  possessing  a  very  penetrating,  persistent,  and  disagreeable  odor  and 
taste,  practically  insoluble  in  water,  soluble  in  alcohol,  ether,  fixed  oils,  glycerin, 
etc.  0.25  G.  (4  grs.);  B.  P.,  |-3  grs.  in  pills  or  capsules. 
Unguentum  Iodoformi  (U.  S.  P.,  B.  P.),  contains  10  per  cent,  iodoform. 
Thymolis  lodidum  (U.  S.  P.),  Aristol  (C6H2'CH3"C3H7'OI)2,  a  yellowish- 
brown  powder;  tasteless,  odorless,  insoluble  in  water. 

lodolwn  (U.  S.  P.),  C^L'NH,  a  light  grayish-brown  crystalhne  powder,  taste- 
less, odorless,  insoluble  in  water.     Dose,  0.25  G.  (4  grs.). 

The  Sozoiodalate  of  potassium  is  slightly  soluble  in  water,  the  sodium  and 
zinc  salts  more  soluble.  Mercury  forms  an  insoluble  salt  which  may  l)e  dis- 
solved by  the  addition  of  sodium  chloride. 

Therapeutic  Uses. — Iodoform  has  been  used  to  a  very  limited  extent 
internally  in  the  treatment  of  syphilis,  and  as  an  intestinal  disinfectant. 
It  is  chiefly  employed  in  surgical  treatment  as  an  application  to  wounds, 
skin  diseases  and  burns.  In  granulating  surfaces  with  a  profuse  secretion, 
and  in  slowly  healing  abscess  cavities,  it  seems  to  be  especially  valuable. 
It  may  be  applied  as  a  dusting  powder,  as  an  ointment,  or  in  gauze 
or  bandages  saturated  with  it.  It  has  been  shown  that  it  has  very  weak 
antiseptic  properties,  and  many  surgeons  take  the  precaution  of  dis- 
infecting the  powder  before  applying  it,  and  use  it  for  its  eft'ect  on  the 
tissues  of  the  wound  and  not  for  its  effects  on  the  germs.  Applied  in 
ordinary  quantity  to  small  surfaces  it  seems  to  be  a  perfectly  safe 
remedy,  cases  of  poisoning  occurring  only  when  large  cavities  are  plugged 
with  it,  or  when  it  is  applied  to  very  large  absorbent  surfaces. 

Iodoform  has  been  credited  with  some  specific  action  in  tubercular 
disease,  but  has  proved  almost  inert  toward  the  bacillus.  The  favor- 
able results  in  the  local  treatment  of  tubercular  abscesses,  laryngeal 
ulcers  and  similar  conditions  may  with  greater  probability  be  attributed 
to  its  action  on  the  granulation  tissue.  In  syphilitic  ulcers  and  chancres, 
iodoform  has  been  used  very  largely  and  with  good  effects. 


152  SUBSTANCE&  ACTING  LOCALLY 

lodol  may  he  used  as  a  sul)stitut('  for  iodoform,  and  is  ai)i)lird  in 
the  same  way.  The  sozoiodolates  arc  used  as  i)o\vders  or  ()intments, 
or  in  the  case  of  the  sodimii,  zinc  and  mercury  salts,  in  sohition. 
Tlie  last  is  poisonous,  and  is  comparable  to  corrosive  sublimate  in 
its  effects. 

Bibliography. 

Binz.  Arch.  f.  cxp.  Path.  u.  Pharm.,  viii,  p.  309;  xiii,  p.  11.3.  Virchow's  Anhiv,  Ixxxix, 
p.  389. 

Behring.    Deutsch.  med.  Woch.,  1882,  p.  278. 

Zeller.    Arch.  f.  klin.  Chirurg.,  xxviii,  p.  590.    Zts.  f.  physiol.  Choniie,  viii.  p.  70. 

Mulzer.     Ztschr.  f.  exp.  Path.  u.  Ther.,  i,  p.  446. 

Falkson.     Arch.  f.  klin.  Chirurg.,  xxviii,  p.  112. 

Neisser.    Virchow's  Archiv,  ex.,  p.  381. 

Block.    Zeitschr.  f.  exp.  Path.  u.  Ther.,  ix,  p.  509. 

Marcus.     Berl.  khn.  Woch.,   1886,  p.  342.     (lodol.) 

Satller.    Fortschr.  d.  Med.,  1887,  p.  362.     (lodol.) 

Lomry.    Arch.  f.  klin.  Chirurg.,  liii,  p.  787. 

Meyer.    Ibid.,  Iv,  p.  676. 


II.  Antiseptics  Used  Chiefly  in  Skin  Diseases. 
1.  Pyrogallol. 

Pyrogallol,  C6H3(OH)3  the  only  trioxybenzol  that  has  been  largely 
used,  produces  nervous  symptoms  resembling  those  of  carbolic  acid,  when 
given  in  very  large  doses  to  animals.  In  the  cases  of  poisoning  which 
have  been  observed  in  man,  the  symptoms  arose  almost  exclusively 
from  changes  in  the  blood  corpuscles.  The  red-blood  cells  become 
shrunken  and  angular  and  lose  most  of  their  haemoglobin,  which  escapes 
into  the  plasma  and  is  changed  into  methwrnoglobin;  the  blood  there- 
fore assumes  a  chocolate-brown  color,  Avhich  \\va\  be  detected  in  the 
living  animal  by  the  discoloration  of  the  skin  and  mucous  membranes. 
If  the  intoxication  is  not  too  acute,  icterus  follows,  and  haemoglobin 
and  methirmoglobin  are  excreted  in  the  urine.  In  the  blood,  fragments 
of  red  cells  and  "  shadows,"  or  red  cells  deprived  of  their  coloring  matter, 
are  seen  in  large  numbers,  and  the  spectrum  of  methaniioglobin  can  be 
obtained  easily.  The  kidneys  are  also  afl'ectcd,  aiid  the  resulting  neph- 
ritis is  indicated  by  the  presence  in  the  urine  of  albumin,  epithelium 
and  casts,  along  with  the  products  of  the  decomposition  of  the  blood. 
The  nephritis  may  lead  to  ura^mic  convulsions,  which  are  sometimes 
accompanied  by  the  nervous  tremors  characteristic  of  this  series,  and 
also  by  dyspnoea  and  cyanosis  from  the  lack  of  luemogl()bin  in  the  blood. 
The  formation  of  methanioglobin  is  due  to  the  reducing  properties  of 
the  drug.  I'yogailol  is  excreted  in  part  in  combination  with  sulphuric 
acid  in  the  uriii(>.  in  part  as  luiknown  oxidized  products,  which  give 
the  urine  a  dark  brown  or  black  color,  even  wIumi  no  blood  ])igments 
are  contained  in  it. 

The  skin  is  dyed  brown  wIkmi  ])yrogall()l  is  applied  to  it.  from  the 
I)roducts  of  oxidation  formed. 


ANTISEPTICS  AND  DISINFECTANTS  153 

Pi/rogallol  (U.  8.  P.),  pyrogullic  acid  (C6H.-i(OH)3,  light,  colorloss  crystals 
t)r  lamin*  when  freshly  prepared,  which  rajiidlj-  assume  a  dai-ker  color  on 
exposure  to  light  and  air.  It  is  very  soluble;  in  watei-  and  reduces  the  salts 
of  the  heav}^  metals  even  in  the  cold.    It  is  used  only  externally. 

Pyrogallol  is  used  in  the  treatment  of  several  forms  of  skin  disease, 
especially  in  psoriasis,  in  which  it  is  appKed  in  ointment  (5-20  per 
cent.).  It  is  dangerous  to  apply  it  to  very  large  surfaces,  however, 
and  many  authorities  therefore  advise  the  use  of  chrysarobin  in  its 
stead.  Pyrogallol  ought  never  to  be  used  internally.  Its  curative 
action  in  skin  diseases  may  be  due  to  its  slight  irritant  and  antiseptic 
properties,  but  is  referred  by  some  to  its  reducing  action. 

Bibliography. 

Wedl.    Wiener  Sitzungsber,  Ixiv,  p.  405. 

Neisser.    Zts.  f.  klin.  Med.,  i,  p.  88. 

Weyl  u.  Anrep.    Arch.  f.  Anat.  u.  Phys.,  1880,  p.  234. 

2.  Chrysarobin. 

Chrysarobin  is  a  mixture  in  varying  proportions  of  several  bodies 
which  are  closely  related  to  the  active  principles  of  the  anthracene 
purgatives.  It  is  found  in  an  impure  form  (Goa  powder)  in  cavities  in 
the  Andira  araroba,  a  tree  growing  in  India  and  Brazil.  Chrysarobin 
applied  to  the  skin  in  a  concentrated  form,  or  in  susceptible  persons, 
causes  itching,  redness  and  swelling,  less  frequently  papular  or  pustular 
eruptions;  the  skin  and  clothing  are  stained  a  reddish-brown  color 
where  it  is  applied.  When  swallowed,  chrysarobin  acts  as  a  gastro- 
intestinal irritant,  causing  vomiting  and  purging;  some  of  it  is  absorbed, 
and  in  its  excretion  by  the  kidneys  it  causes  in  the  rabbit  nephritis 
with  albumin  and  even  blood  in  the  urine.  In  man,  slight  albuminuria 
has  been  observed  in  some  instances  after  its  application  to  the  skin; 
in  animals  the  epithelium  of  the  renal  tubules  has  been  found  to  be 
necrosed,  the  glomeruli  being  less  frequently  affected.  It  was  antici- 
pated that  it  would  undergo  oxidation  to  chrysophanic  acid  in  the 
body,  and  this  is  true  for  a  part  of  that  absorbed,  but  most  of  it  passes 
through  the  tissues  unchanged. 

Chrysarobinum  (U.  S.  P.,  B.  P.),  a  substance  obtained  from  Goa  powder, 
which  is  found  in  the  trunk  of  Andira  araroba.  It  consists  for  the  most  part 
of  chrj^sarobin,  but  contains  some  chrysophanic  acid. 

Unguentum  Chrysarobini  (B.  P.),  4  per  cent.  (U.  S.  P.),  6  per  cent. 

Chrysarobin  is  used  in  skin  diseases,  especially  in  psoriasis,  in  which 
it  is  applied  in  ointment.  Its  effects,  like  those  of  pyrogallol,  have 
been  ascribed  to  its  reducing  action.  Chrysophanic  acid  might  be 
used  also  for  this  purpose  were  its  isolation  not  attended  with  such 
expense.  Some  confusion  has  arisen  from  chrysarobin  having  been  at 
first  supposed  to  be  chrysophanic  acid. 


154  SUBSTANCES  ACTING  LOCALLY 


3.  Naphthol. 

The  iiaplitliols,  ('luHvOII,  reseni})le  carbolic  acid  in  their  antiseptic 
action  but  are  much  less  soluble  and  less  corrosive.  Alpha-naphthol 
has  been  found  to  })e  more  strongly  antiseptic  than  the  beta  compound, 
and  may  be  more  poisonous,  as  is  generally  stated,  but  no  satisfactory 
investigation  has  appeared  regarding  this  point.  Beta-naphthol  is 
several  times  as  strongly  germicidal  as  carbolic  acid,  and  is  the  form 
used  in  therapeutics. 

Large  doses  of  the  Naphthols  induce  symptoms  similar  to  those  of 
carbolic  acid  poisoning,  except  that  in  the  dog  no  convulsions  have 
been  observed,  and  in  the  other  mammals  they  seem  less  pronounced. 
They  are  irritating  to  the  mucous  membranes  when  they  come  in  con- 
tact with  them  in  solution  or  in  vapor;  thus  they  cause  sneezing  and 
coughing  when  applied  to  the  respiratory  passages, .  and  in  the  course 
of  excretion  induce  pain  in  the  bladder  and  urethra  with  strangury 
and  swelling  of  the  mucous  membrane.  Injected  subcutaneously  or 
absorbed  from  the  alimentary  canal  in  animals,  they  induce  acute 
nephritis  with  the  appearance  of  albumin  and  haemoglobin  in  the 
urine,  and  some  nephritis  has  been  caused  in  man  from  their  external 
application.  They  seem  to  have  less  effect  on  the  circulation  and 
respiration  than  the  other  aromatic  antiseptics,  but  resemble  them  in 
tending  to  destroy  the  red  cells  of  the  blood. 

Occasionally  naphthol  has  given  rise  to  imperfect  sight  and  partial 
retinal  degeneration  in  man,  and  changes  in  the  eye  have  been  observed 
repeatedly  in  experiments  on  animals  in  which  naphthol  was  absorbed. 
The  retina  is  seen  to  be  dotted  over  with  bright  points  or  to  contain 
large  yellow  plaques.  Atrophy  of  the  optic  nerve  may  follow  or  sub- 
retinal  effusion,  and  cataract  has  been  developed  in  some  experiments, 
from  an  inflammatory  infiltration  beginning  in  the  ciliary  body  and 
iris  and  extending  into  the  lens  and  finally  into  the  posterior  surface 
of  the  cornea.  While  the  ocular  eftects  in  man  have  never  reached  this 
intensity,  Iloeve  has  observed  some  defects  of  vision  induced  by  the 
use  of  naphthol  internally  or  externally,  and  cautions  against  its  pro- 
longed use. 

The  naphthols  are  excreted  in  the  urine  in  combination  with  glycuronic 
and  sulphuric  acids,  and  these  combinations  and  their  oxidized  products 
give  the  urine  a  reddish-brown  color  which  may  become  deeper  on 
exposure  to  the  air. 

Naphlh(tliit,  CioHs,  the  hydrocarbon  from  which  naphthol  is  derived,  is  less 
soluble  and  docs  not  give  rise  to  acute  syinptonis  in  animals,  but  after  pro- 
longed treatment  with  it  animals  suffer  from  diarrhoea  and  nephritis,  with 
albumin  and  casts  in  the  urine.  The  same  changes  in  the  retina,  are  induced 
by  nai)hthalin  as  by  the  naphthols.  The  antiseptic  value  of  najihtlialiu  is  small, 
but  it  is  oxidized  to  naphtiiols  in  the  tissues  and  these  acquire  a  toxic  action. 
It  is  excreted  in  tiie  lU'ine  as  nai)hihol  and  further  oxidation  products,  in  com- 
l)ination  with  glycuronic  and  sulphuiic  acid. 


ANTISEPTICS  AND  DISINFECTANTS  155 

BETANArHTHOL  (U.  S.  P.),  Naphthol  (B.  P.),  Beta-naphtol  (C10TT7OTT), 
wliite  or  vellowish-white,  insoluble  crystals  or  powder,  with  a  faint  i)hcnol 
odor  and  a  hot  taste.    0.25  G.  (4  grs.)  B.  P.,  3-10  grs. 

Therapeutic  Uses. — Beta-naplithol  was  at  first  introduced  as  an  external 
application  in  various  forms  of  skin  disease,  in  which  it  is  used  in  ointment 
(5-10  per  cent.).  Naphthalin  was  also  employed  in  the  same  way,  but 
has  not  proved  so  popular.  Beta-naphthol  has  also  been  given  internally 
as  an  intestinal  disinfectant,  but  has  not  been  efficacious.  It  has  been 
employed  as  an  anthelmintic  to  a  limited  extent,  and  apparently  with 
some  success,  though  it  has  not  proved  so  reliable  as  some  of  the  older 
drugs  used  for  this  purpose.  Naphthol  is  more  largely  used  than  naph- 
thalin in  internal  medication,  and  may  be  prescribed  as  a  powder  or  in 
capsules.  Naphthalin  and  naphthol  ought  to  be  avoided  in  irritation  of 
the  kidneys,  bladder  or  urethra. 

Bibliography. 

Willenz.    Therap.  Monatsheft,  1888,  p.  20. 
Baatz.     Centralbl.  f.  inn.  Med.,  1894,  p.  857. 
Lesnik.    Arch.  f.  exp.  Path.  u.  Pharm.,  xxiv,  p.  168. 
Magnus.     Therap.  Monats.,   1887,  p.  387. 
Klingmann.     Virchow's  Arch.,  cxlix,  p.  12. 
V.  d.  Hoeve.     Arch.  f.  Ophthalmol.,  liii,  p.  74. 
Edlefsen.    Arch.  f.  exp.  Path.,  liii,  p.  429. 

4.  Resorcin. 

The  three  dioxybenzols — resorcin,  pyrocatechin  and  hydroquinone — resem- 
ble carbolic  acid  in  their  effects,  but  produce  a  more  intense  stimulation 
of  the  central  nervous  sj^stem,  for  convulsions  have  been  observed  in  man 
after  their  use.  This  is  especially  true  for  the  last  two,  resorcin  being  much 
less  toxic  than  these.  Resorcin  seems  to  be  equally  or  more  strongly  anti- 
septic than  phenol,  and  is  somewhat  less  poisonous,  while  the  others  are 
more  dangerous;  it  is  less  irritant  and  caustic  than  carbolic  acid.  All  three 
dioxybenzols  are  excreted  in  the  urine  in  combination  with  sulphuric  and 
glycuronic  acids.  They  are  in  part  subjected  to  further  oxidation,  leading  to 
coloration  of  the  urine  similar  to  that  seen  in  carbolic  acid  poisoning. 

Resorcinol  (U.  S.  P.)  Resorcinum  (B.  P.),  resorcin,  metadioxybenzol  (CcH4- 
(OH2)),  colorless,  very  soluble  crystals,  with  a  faint  aromatic  odor.  0.125  G. 
(2grs.);B.  P.  1-5  grs. 

Resorcin  has  been  applied  in  ointment  (5-10  per  cent.)  in  skin  diseases,  and 
has  been  injected  in  cystitis  and  gonorrhoea  in  solution  (1-3  per  cent.),  but  in 
both  cases  is  liable  to  produce  irritation  and  pain.  As  an  internal  remedy  it 
was  formerly  used  as  an  antipyretic  and  as  an  intestinal  disinfectant  but  has 
fallen  into  complete  disuse. 

Bibliography. 

Andeer.    Centralbl.  f.  d.  med.  Wis.,  1881-1889. 
Marlin.     Therap.  Gaz.,  1887,  p.  289. 
Surbeck.     Deutsch.  Arch.  f.  klin.  Med.,  xxxii,  p.  515. 
Danilewsky.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxv,  p.  105. 

5.  Tar. 

Long  before  carbolic  acid  and  its  congeners  were  known,  tars  and  other 
crude  preparations  enjoyed  a  reputation  in  the  treatment  of  woiuuls, 


156  SUBSTANCES  ACTING  LOCALLY 

and  some  of  these  have  been  retained  in  medicine  and  are  widely  used. 
Amoni?  these  the  tar  obtained  by  the  dry  (Hstillation  of  (Hfferent  woods 
is  inchided;  its  constituents  vary  with  the  source,  l)ut  tlic  creosols 
(CcHsCIIs.OII.OCII;)),  guaiacols  (('oH.OI I .()( 'II;,),  and  otlicr  less  poison- 
ous aromatic  compounds  are  present  in  larger  quantity  than  the  phenols 
and  dioxybenzols,  and  wood-tar  is  therefore  less  poisonous  than  carbolic 
acid,  and  its  simpler  homologues.  At  the  same  time  these  higher  com- 
binations seem  to  have  the  same  antiseptic  powers  as  the  simpler 
benzol  derivatives,  so  that  several  of  the  crude  preparations  possess 
considerable  value  in  surgery  and  medicine. 

Prepakations. 

Fix  Liquida  (U.  S.  P.,  B.  P.),  tar,  is  obtained  from  the  wood  of  Pinus  palus- 
tris  and  other  species  of  Pinus  by  destructive  distillation,  and  contains  a  very 
large  number  of  aromatic  bodies  mixed  with  others  of  less  importance. 

Oleum  Picis  Liquidce  (U.  S.  P.),  oil  of  tar,  is  a  volatile  fluid  distilled  from 
tar,  and  consists  almost  entirely  of  guaiacols  and  their  compounds.  0.2  c.c. 
(3  mins.). 

Syrupus  Picis  Liquidce  (U.  S.  P.),  syrup  of  tar,  4  c.c.  (Ifl.  dr.). 

Unciuenlum  Picis  Liquidce  (U.  S.  P.,  B.  P.). 

Tar  has  also  been  used  with  considerable  success  as  an  antiseptic  in 
skin  diseases,  in  which  it  may  be  applied  either  alone  or  as  an  ointment. 
It  is  only  slightly  irritating  to  the  skin,  and  some  absorption  occurs, 
as  is  often  seen  by  the  dark  color  of  the  urine.  Internally  it  has  been 
used  occasionally  as  an  anthelmintic  and  intestinal  disinfectant,  much 
more  frequently  as  an  "expectorant"  in  cough  mixtures.  AVhether 
it  has  any  effects  on  the  lungs  in  these  cases  may  be  questioned.  It  is 
generally  given  as  the  syrup. 

Tar  is  a  valuable  disinfectant,  which  is  very  generally  available 
and  is  much  cheaper  than  the  purer  bodies  of  the  aromatic  series.  It 
may  be  used  for  the  disinfection  of  excrementa,  latrines,  etc.,  where 
the  cost  of  even  crude  carbolic  acid  would  be  prohibitive. 

Bibliography. 

Ncncki  u.  Sieber.     Arch.  f.  exp.  Path.  ii.  Pharm.,  xxxiii,  p.  1. 
Slrutn.     Arch.  d.  Pharmacie,  ccxxxvii,  p.  525. 

Icltlhyol  is  derived  from  the  tar  of  a  bituminous  shale  which  is  found  in  the 
Tyrol,  and  which  contains  the  remains  of  many  fossil  iishes.  It  has  a  high 
percentage  of  sulphur,  and  ])ossesscs  some  antiseptic  action,  altliough  it  is 
Ix'lieved  to  l^e  less  i)()werful  than  carbolic  acid.  Applied  to  the  .skin,  ichthyol 
causes  slight  irritation,  whicli  is  ajipanMitly  of  benefit  in  some  cutaneous  tliseases, 
and  it  has  therefore  been  used  extensively  for  this  action.  A  certain  amount 
of  absori)tion  occurs  when  it  is  rublx'd  into  the  skin,  for  the  sulphur  of  the  urine 
has  l)een  found  to  be  augmented.  Taken  internally  in  large  quantities,  it  acts 
as  a  gastric  and  intestinal  irritant  and  ])i()duces  diairluea,  Imt  it  is  only  \'ery 
feebly  poisonous. 

Ichtliyol  has  been  strongly  reconunended  in  the  treatment  of  a  number  of 
skin  diseases,  including  (^rysipelas.  It  is  generally  used  as  an  ointnu'iit  con- 
taiiiiiig  ('(|ii;d  i)arls  of  idilhydl  and  of  vaseline,  but  may  be  used  in  10  pel'  cent. 


ANTISEPTICS  AND  DISINFECTANTS  157 

or  even  weaker  dilution.  Ichthyol  has  been  enthusiastically  praised  as  a  remedy 
in  the  most  di\'erse  conditions,  and  it  seems  probable  that  its  sphere  of  utility 
will  be  verj^  much  more  restricted  in  the  future,  if  it  does  not  disappear  from 
therapeutics  entirel}\ 

INIany  other  drugs  applied  to  the  skin  may  exercise  some  germicidal 
action  along  with  their  other  properties,  but  are  discussed  elsewhere. 
(See  zinc,  lead,  sulphur  ointments.) 


III.  Intestinal  Disinfectants. 

Salol. 

Salol,  or  phenyl-salicylate  (C6H4  OH  COO  CeHs),  may  be  taken  as  a  type 
of  the  drugs  used  to  disinfect  the  intestine,  or  at  any  rate  to  retard  the 
growth  of  bacteria  in  the  contents  and  the  wall  of  the  bowel.  It  is  a 
very  insoluble,  crystalline  body,  which  has  little  or  no  local  action 
in  the  mouth  or  stomach,  but  is  decomposed  in  the  intestine  by  the 
fat-splitting  ferment  of  the  pancreatic  juice.  Some  decomposition  also 
appears  to  occur  in  the  stomach,  at  any  rate  under  certain  conditions. 
The  products  of  its  decomposition,  salicylic  and  carbolic  acids,  are 
absorbed  and  produce  their  usual  effects.  Salol  is  used  chiefly  as  a 
substitute  for  salicylic  acid,  but  the  formation  of  phenol  from  it  in  the 
body  must  not  be  overlooked,  for  in  several  cases  of  dangerous  poisoning 
which  have  been  observed  under  it,  the  symptoms  were  those  character- 
istic of  carbolic  acid,  and  the  urine  became  dark  in  color  from  the 
phenol  oxidation  products.  In  moderate  quantities,  salol  produces 
the  disturbances  of  hearing  observed  under  salicylic  acid,  without  any 
symptoms  of  carbolic  poisoning. 

Other  salicylic  acid  compounds,  similar  to  salol,  are  hetol  or  naphthalol 
(the  beta-naphthol  salicylate),  cresalol  (cresol  salicylate),  ihymosalol 
(from  thymol),  guaiacohalol.  They  are  less  poisonous  than  salol,  but 
have  not  been  largely  used, 

Salol  (B.  P.),  Phenylis  Salicylas  (U.  S.  P.),  phenyl  salicylate  (CeHi- 
OHCOOCeHs),  a  white  crj'stalline  powder,  odorless  or  faintl}^  aromatic,  almost 
tasteless,  almost  insoluble  in  water,  decomposed  by  the  pancreatic  juice  into 
saHcylic  acid  and  phenol.  0.5  G.  (7^  grs.);  B.  P.,  5-20  grs.,  in  powder  or 
capsule. 

Salol  has  been  used  to  lessen  putrefaction  in  the  bowel,  and  even 
to  act  upon  the  bacilli  of  typhoid  fever  and  of  tubercle  infecting  the 
intestinal  wall.  Kumagawa,  however,  states  that  the  putrefaction 
in  the  bowel  as  measured  by  the  indican  in  the  urine  is  unchanged  by 
its  administration,  and  he  foimd  enormous  numbers  of  bacteria  in  the 
faeces  afterward.  It  certainly  seems  of  little  value  in  typhoid  fever 
or  in  tuberculosis  of  the  intestine.  Intestinal  calculi  have  been  formed 
in  a  few  instances  from  prolonged  treatment  with  salol,  which  failed 
to  be  decomposed  in  the  intestine  and  formed  masses  of  considerable 
size. 


158  •  SUBSTANCES  ACTING  LOCALLY 

Salol  has  been  used  to  diagnose  stenosis  of  the  pylorus,  as  it  was  supposed 
that  in  these  cases  the  reaction  of  sahcyhc  acid  in  the  urine  would  be  delayed 
when  salol  was  given.  But  some  salol  is  absorbed  from  the  stomach,  and  the 
interval  before  salicylic  acid  appears  in  the  urine  varies  widely  in  normal  per- 
sons, so  that  the  test  is  of  little  value. 

Salol  has  some  value  as  a  genito-urinary  disinfectant,  partly  owing  to  the 
salicylic  acid  component  and  partly  to  the  phenol  developed. 

It  is  used  as  a  substitute;  for  salicylic  acid  in  rheumatic  fever,  and  has  the 
advantage  of  being  tasteless  and  of  producing  no  irritation  in  the  stomach. 
On  the  other  hand,  the  considerable  amount  of  carbolic  acid  freed  by  its  decom- 
position has  given  rise  to  poisoning  in  some  cases.  Externally  it  is  of  little 
or  no  value  as  an  antiseptic,  as  it  is  only  active  when  decomposed  by  the  microbes 
which  it  is  designed  to  destroy. 

Bibliography. 

Nencki.    Arch.  f.  exp.  Path.  u.  Pharm.,  xx,  p.  367. 
Lesnik.      Ibid.,    xxiv,    p.    167. 

Other  Intestinal  Disinfectants. 

Most  of  the  drugs  possessing  disinfectant  properties  have  been  used 
at  one  time  or  another  in  the  hope  of  reducing  the  intestinal  putrefaction, 
but  have  generally  been  abandoned  after  a  shorter  or  longer  vogue. 
Among  these  may  be  mentioned  carbolic  acid,  corrosive  sublimate, 
resorcin,  naphthol  and  thymol.  As  has  been  stated  (p.  128),  there  is 
little  prospect  of  destroying  bacteria  imbedded  in  the  wall  of  the  intestine 
without  serious  injury  to  the  mucous  membrane.  On  the  other  hand 
putrefaction  of  the  contents  of  the  bowel  is  better  treated  by  their 
evacuation  than  by  attempts  to  retard  the  process  in  the  body. 

IV.  Genito-urinary  Antiseptics. 

1.  Volatile  Oils. 

A  group  of  volatile  oils  is  used  chiefly  for  genito-urinar}^  disinfection. 
The  best  known  of  these  are  the  Oils  of  Copaiba,  'Cuhchs  and  Sandalwood, 
which  resemble  each  other  closely  in  character.  Oil  of  cubebs  and 
oil  of  copaiba  contain  a  large  proportion  of  sesquiterpene  (C15H24), 
and  the  oil  of  sandalwoood  has  two  oxidized  substances  (santalol  and 
santalal),  which  can  be  reduced  to  a  sesquiterpene  identical  with  that 
of  copaiba.  In  copaiba  the  volatile  oil  is  associated  with  one  or  more 
resinous  acids,  and  in  cubebs  there  is  in  addition  to  resinous  acids  a 
bitter  substance,  Cubebin,  which  is  not  absorbed  from  the  stomach  and 
bowel,  however,  and  is  entirely  inactive.  Cubebs  and  copaiba  have 
long  been  used  as  genito-urinary  disinfectants,  while  sandalwood  oil 
is  a  more  recent  addition  to  the  group,  which  is  less  disagreeable  to 
take  and  has  less  tendency  to  disturb  the  disgestion.  These  oils  have 
the  irritant  effects  on  the  skin,  stomach  and  intestine  common  to  the 
class  of  volatile  oils  (p.  57),  are  absorbed  readily  and  are  excreted 
partly  by  the  lungs,  but  chiefly  by  the  kidneys  in  combination  with 


ANTISEPTICS  AND  DISINFECTANTS  159 

glucuronic  acid;  some  oil  is  unchanged,  some  is  partially  oxidized  in 
the  tissues. 

The  products  of  the  oils  excreted  in  the  urine  appear  to  have  some 
antiseptic  action,  for  the  urine  of  persons  treated  with  them  putrefies 
more  slowly  than  ordinary  urine  and  the  growth  of  many  of  the  more 
common  germs  is  retarded  by  it;  thus  Jordan  found  that  the  urine  was 
powerfully  germicidal  to  a  staphylococcus  after  sandalwood  oil  had 
been  taken,  and  this  action  persisted  even  when  the  urine  was  rendered 
alkaline;  on  the  other  hand  the  colon  bacillus  grew  luxuriantly;  others 
have  found  the  gonococcus  grow  readily  in  media  made  up  with  such 
urine.  Winternitz  therefore  attributes  the  undoubted  efficacy  of  these 
oils  in  gonorrhoea  to  their  lessening  the  inflammatory  exudate  rather 
than  to  their  antiseptic  action,  without  denying  that  the  latter  may 
also  be  of  some  importance. 

In  large  quantities,  these  oils  cause  irritation  in  the  bladder  and 
urethra,  which  leads  to  a  constant  desire  to  micturate,  and  to  much 
pain  and  difficulty  in  doing  so;  sometimes  the  pain  is  so  great  as 
to  lead  to  complete  retention.  When  the  urethra  or  bladder  is  in 
a  state  of  inflammation,  these  symptoms  are  produced  by  even  small 
doses,  so  that  these  oils  are  generally  avoided  in  the  acute  stages  of 
inflammation,  and  only  given  later  when  the  disease  has  passed  into 
the  subacute  or  chronic  stage.  They  are  used  in  some  inflammatory 
affections  of  the  bladder,  but  much  more  extensively  in  gonorrhoea. 

Copaiba  and  cubebs  both  contain  resinous  acids  in  addition  to  the 
volatile  oil,  and  these  possess  considerable  diuretic  powers,  and  are 
also  credited,  along  with  the  oils,  with  some  action  on  the  bronchial 
mucous  membrane,  so  that  they  often  form  constituents  of  "expec- 
torant" mixtures,  prescribed  to  lessen  the  secretion  of  the  bronchi. 
These  resins  are  excreted  in  the  urine,  and  are  precipitated  by  the 
addition  of  acids;  this  precipitate  has  sometimes  been  mistaken  for 
albumin,  but  can  easily  be  distinguished  from  it  by  the  addition  of 
alcohol,  which  redissolves  the  resin  but  not  the  protein.  The  urine  is 
often  found  to  reduce  Fehling's  solution  from  the  glycuronic  acid 
combined  with  the  oil.  The  oil  of  sandalwood  is  excreted  more  rapidly 
than  the  others.  Copaiba  and  cubebs  are  less  irritant  to  the  stomach 
than  many  of  the  other  volatile  oils,  but  after  their  prolonged  adminis- 
tration (especially  in  the  case  of  copaiba)  symptoms  of  gastric  dis- 
turbance sometimes  appear  in  loss  of  appetite  and  uneasiness  in  the 
stomach.  Sandalwood  oil  is  said  to  be  less  irritant  than  the  others. 
Occasionally  skin  eruptions  occur  after  the  use  of  these  oils;  they  are 
generally  of  the  nature  of  urticaria,  sometimes  of  erythema  nodosum, 
and  only  very  rarely  is  eczema  seen.  The  cause  of  these  skin  eruptions 
is  unknown,  but  they  may  be  due  to  the  gastric  disturbance. 

Preparations. 

Copaiba  (U.  S.  P.,  B.  P.),  Balsam  of  Copaiba,  Copaiva,  the  oleoresin  of 
Copaiba  Langsdorffii  and  of  other  species  of  Copaifera.  Dose,  1  c.c.  (15  mins.) ; 
B.  P.,  i-1  fl.  dr. 


IGO  SUBSTANCES  ACTING  LOCALLY 

Oleum  CoPAiBiE  (U.  S.  P.,  B.  P.),  the  oil  freed  from  tlie  rcsiii  bj^  distilla- 
tion, 0.5  c.c.  (8  mins.);    B.  P.,  5-20  inins. 

Cubeba  (U.  S.  P.),  Cubebae  Fructus  (B.  P.),  Cubebs,  the  unripe  fruit  of 
Piper  Cubeba.     1  G.  (15  gi'S-)- 

Oleum  Cubeb.e  (U.  S.  P.,  B.  P.),  0.5  c.c.  (8  mins.);   B.  P.,  5-20  mins. 

Oleoresina  Cubeb.e  (U.  S.  P.),  0.5  G.  (7^  grs.). 

Trnchisci  CubeJxv  (U.  S.  P.). 

Oleum  Santali  (U.  S.  P.,  B.  P.),  Sandalwood  oil,  distilled  from  the  wood 
of  Santalum  album.    Dose,  0.5  c.c.  (8  mins.);   B.  P.,  5-30  mins. 

Santalol  and  santalal  and  some  of  their  compounds  have  been  introduced  as 
gonosan  and  sanhjl  (santalol  salicylate),  etc. 

Therapeutic  Uses. — As  has  been  mentioned,  these  drugs  find  their 
most  extensive  application  in  the  subacute  stages  of  cystitis  and  gonor- 
rhoea. They  are  also  used  in  bronchial  disease  with  an  excessive  flow 
of  mucopurulent  secretion;  less  often  copaiba  is  prescribed  along 
with  other  diuretics  to  promote  the  secretion  of  urine.  The  cubeb 
lozenges  are  sucked  in  hoarseness  and  relaxed  sore  throat,  and  often 
give  relief  owing  to  the  pungent  peppery  action. 

In  gonorrhcpa  the  therapeutic  agent  is  undoubtedly  the  volatile  oil, 
the  resin  having  little  or  no  antiseptic  action.  The  oils  and  the  oleo- 
resins  are  often  administered  in  capsules,  as  they  have  an  mipleasant 
odor  and  taste,  especially  those  of  copaiba.  They  may  also  be  given 
as  emulsions,  and  cubebs  is  sometimes  prescribed  as  a  powder  suspended 
in  mucilage. 

Several  other  oils  have  been  used  as  substitutes  for  Copaiba  and  Cubebs. 
Among  these  may  be  mentioned  Gurjun  Balsam,  which  is  obtained  from  Dip- 
terocarpus  alatus,  and  contains  a  sesquiterpene  and  a  resin.  It  has  been  used 
in  gonorrluca  and  as  a  local  ajiplication  in  leprosy.  Various  peppers  have 
been  employed  as  substitutes  for  culicljs  in  gonorrhoea,  among  them  Motico, 
but  they  have  not  proved  so  useful  as  the  three  typical  oils. 


Bibliography. 

Bernalzik.    Vierteljahisohrift  f.  prakt.  Heilkunde,  Ixxxi,  p.  9,  and  c,  p.  239. 

Quincke.    Arch.  f.  exp.  Path.  u.  Pharm.,  xvii,  p.  273. 

Heffter.    Ibid.,  xxxv,  p.  3G9. 

Winternitz.    Ibid.,  xlv,  p.  163. 

Kara.     Ibid.,  xlvi,  p.  242. 

Hildchrandt.     Ztsclir.  f.  physiol.  C'hem.,  xxxvi,  p.  442. 

Sachs.    Wiener,  kliii.  Woch.,  xv,  p.  442. 

Jordan.     Brit.  Med.  Journ.,  1913,  ii,  p.  648. 

See  also  the  bibliography  of  the  volatile  oils  in  general. 

2.  IIexametiiylentetramine,  Urotuopine. 

lT()tr()i)ine,  or  hexamethylentetramine  (  (CHo)6N.i),  has  no  important 
action  itself,  but  is  of  interest  from  its  liberating  formaldehyde  in 
the  course  of  its  excretion  in  the  urine;  formaldehyde  is  a  powerful  dis- 
infectant, and  the  small  quantities  liberated  from  urotropine  are  suflicient 
to  prevent  j)utr('facti(>M  of  the  urine  for  many  hours.  It  seems  superior 
to  any  other  urinary  antiseptic,  microbes  in  the  urine  decreasing  in 


ANTISEPTICS  AND  DISINFECTANTS  161 

miiuber  or  sometimes  disappearing  altogether  within  a  few  hours  of 
its  administration.  Formaldehyde  is  formed  from  urotropin  only  in 
acid  urine,  and  if  the  urine  is  alkaline  urotropine  has  no  disinfectant 
action  in  the  urinary  passages;  when,  however,  in  those  cases  the 
reaction  of  the  urine  is  rendered  acid  by  the  administration  of  acid 
phosphates,  formaldehyde  is  formed  from  urotropine  and  satisfactory 
results  follow.  Urotropine  is  readily  soluble  and  permeates  freely  into 
most  organs  and  secretions  of  the  body;  thus  it  has  been  found  in  the 
bile,  pancreatic  juice  and  cerebrospinal  fluid,  and  this  has  suggested  its 
use  in  infections  of  these  fluids.  But  there  is  no  evidence  that  formal- 
dehyde is  liberated  from  it  anywhere  except  in  acid  urine,  and  there  is 
equally  little  ground  for  believing  that  urotropine  is  of  benefit  in  infections 
of  the  gall-bladder,  pancreas,  or  central  nervous  system.  No  symptoms 
arise  from  ordinary  doses  of  urotropine,  but  large  quantities  have 
ocqasionally  given  rise  to  pain  and  discomfort  in  the  bladder,  and  more 
rarely  to  h?ematuria;  the  irritant  here  is  not  the  urotropine  itself  but 
the  formaldehyde  liberated  by  it.  Formaldehyde  forms  some  soluble 
combinations  with  uric  acid,  and  this  suggested  the  use  of  urotropine 
in  gravel,  calculus,  gout,  and  similar  conditions,  but  the  results  have 
been  disappointing. 

Hexamethylexamixa  (U.  S.  p.),  Hexamixa  (B.  P.),  Urotropixe 
(  (CH2)6N4),  is  a  white  crystalline  powder,  very  soluble  in  water  and 
giving  off  formaldehyde  in  acid  solution.  Dose,  0.25  G.  (4  grs.),  5-15 
grs.,  B.  P. ;   to  be  taken  in  a  glass  of  water. 

Urotropine  is  used  in  cystitis  and  urethritis  and  to  destroy  typhoid 
bacilli  in  cases  in  which  they  are  eliminated  by  the  kidney.  It  may 
also  be  given  as  a  prophylactic  before  a  catheter  is  passed.  In  order 
to  secure  that  the  urine  shall  be  acid,  urotropine  is  often  given  along 
with  acid  sodium  phosphate. 

Numerous  compounds  of  urotropine  have  been  introduced  of  late  5'ears  by 
rival  manufacturers,  but  none  of  these  has  proved  superior  to  the  original  drug, 
and  none  of  them  form  formaldehj'de  in  alkaline  urine. 

Bibliography. 

Nicolaicr.  Zts.  f.  klin.  Med.,  xxxviii,  p.  350;  Deutsch.  Arch.  f.  klin.  Med.,  Ixxxi,  p. 
181 ;    Ixxxviii,  p    168. 

Sollmann.     Journ.  Amer.  Med.  Assoc,  September  5,   1908. 
Richardson.    Journ.  of  Exp.  Med.,  iv,  p.  19. 
Jordan,  Walker.     Brit.  Med.  Journ.,  1913,  ii,  pp.  648,  654. 
Hanzlik  and  Collins.     Arch.  Inter.  Medicine,  1913,  p.  578. 

3.   Minor  Genito-urixary  Antiseptics. 

The  salicylates  have  some  effect  in  retarding  the  growth  of  micro- 
organisms in  the  genito-urinary  tract  and  sodium  salicylate  and  salol 
(p.  157)  have  been  used  for  this  purpose.  Benzoic  acid  and  ammonium 
benzoate  are  also  used  to  disinfect  the  urine,  and,  as  in  the  case  of  sali- 
cylate, act  well  when  it  is  acid,  but  lose  their  effect  largely  when  it  is 
11 


162  SUBSTANCES  ACTING  LOCALLY 

alkaline.  Arhutin,  a  glucoside  contained  in  the  uva  ursi,  is  also  credited 
with  some  antiseptic  properties,  but  is  less  used  now  than  formerly. 
Boric  acid  and  borax  are  both  good  genito-urinary  antiseptics  and 
differ  from  the  other  more  active  drugs  of  this  class  in  retaining  their 
disinfectant  action  when  the  urine  is  alkaline.  Finally  the  urine  is  a 
much  less  favorable  medium  for  bacterial  growth  when  it  is  acid,  and 
anything  which  promotes  the  acidity  (acid  phosphate  or  benzoic  acid), 
has  thus  some  antiseptic  value. 

V.  Antiseptics  in  Pulmonary  Disease. 

Creosote. 

Creosote  may  be  regarded  as  a  wood-tar  from  which  the  more  poison- 
ous phenols  and  the  less  volatile  bodies  have  been  eliminated,  leaving 
guaiacols  and  creosols  as  the  chief  constituents.  Its  action  is  similar 
to  that  of  carbolic  acid,  except  that  it  has  less  tendency  to  induce 
nervous  symptoms,  and  is  less  irritant  and  poisonous.  On  the  other 
hand,  it  seems  at  least  as  strongly  antiseptic  as  carbolic  acid,  and, 
according  to  some  investigators,  far  excels  it  as  a  germicide.  Its 
chief  constituents,  the  Creosols  (C6H3CH3OH.OCH3)  and  Guaiacols 
(C6H4OH.OCH3),  resemble  carbolic  acid  and  the  other  aromatic  phenols 
in  their  action.  They  are  excreted  in  the  urine  for  the  most  part  in  com- 
bination with  sulphuric  and  glycuronic  acids. 

Guaiacol  is  readily  absorbed  from  the  skin  when  rubbed  into  it 
and  considerable  amounts  can  be  regained  from  the  urine  afterwards. 
When  large  quantities  are  thus  taken  up  from  the  skin,  they  often 
cause  a  rai)i{l  fall  of  fever  temperature  with  exhaustion  and  all  the 
symptoms  of  mild  collapse,  followed  by  shivering  and  rigor  and  a 
return  of  the  high  temperature.  This  condition  of  poisoning  is  exactly 
similar  to  that  seen  under  other  benzene  derivatives  of  simple  con- 
stitution. 

Guaiacol  carbonate  ( (C7H70)2C03)  is  almost  insoluble  and  tasteless, 
and  liberates  guaiacol  in  the  intestine. 

Preparations. 

Creosotum  (U.  S.  P.,  H.  P.)  is  obtained  from  wood-tar,  preferably  from 
beech  tar,  and  is  an  almost  colorless,  oily  liquid  with  a  smoky  odor  and  hot, 
burning,  acrid  taste.  It  is  slightly  soluble  in  water,  and  mixes  readily  with 
alcohol.  It  tends  to  darken  in  color  when  ex])osed  to  the  light.  0.2  c.c.  (3 
mins.);  1-5  mins.  B   P 

Aqua  Creusoli  (U.  S.  P.),  a  very  dilute  solution  of  creosote  in  water,  less 
than  1  per  cent.    8  c.c.  (2  fl.  drs.). 

Umjucnhim  Creosoti  (B.  P.),  10  per  cent. 

Creosoti!  may  be  administered  in  i)ills,  cajjsuies,  in  solulioii  in  alcohol  or 
cod-liver  oil,  or  as  a  mixture.  'IMie  \vin<>  of  creo.sote,  wliicli  has  been  a  popular 
niinedy,  contains  it  dissolved  in  \vin(^  along  with  some  Ijrandy  and  tincture  of 
gentian.  It  ought  not  be  allowed  to  reach  the  mucous  nuMiibranes  in  a  con- 
centrated form,  as  it  is  liable  to  irritate  tliem. 


ANTISEPTICS  AND  DISINFECTANTS  163 

Guaiacol  (U..S.  P.,  B  P.)  (CeHi.OH.OCIIs),  colorless  crystals,  or  fluid  with  an 
agreeable  aromatic  odor,  soluble  in  80  parts  of  water  and  in  alcohol.  Dose, 
0,5  c.c.  (S  mins.)  in  solution  in  alcohol  or  cod-liver  oil,  or  in  pills. 

Guaiacolis  Carbonas  (U.  _S.  P.,  B  P.)  (  (C7H70)2C03),  an  almost  tasteless 
powder,  is  given  in  cachets  in  doses  of  1  G.  (15  grs.). 

Therapeutic  Uses. — Creosote  is  comparatively  seldom  used  except 
in  the  treatment  of  pulmonary  phthisis  and  gangrene,  and  chronic 
bronchial  inflammation.  It  is  generally  given  by  the  mouth  in  these 
cases,  but  has  also  been  injected  hypodermically  or  into  the  rectum; 
the  vapor  is  recommended  as  an  inhalation,  and  some  practitioners 
have  injected  creosote  solution  into  the  trachea,  in  order  to  ensure  its 
reaching  the  lungs.  None  of  these  methods  are  believed  to  give  such 
good  results  as  the  ordinary  administration  by  the  mouth.  Guaiacol 
and  guaiacol  carbonate  have  recently  been  substituted  for  the  creosote 
and  are  more  pleasant  forms.  The  carbonate  has  also  been  employed 
as  an  intestinal  disinfectant. 

The  results  of  creosote  medication  are  still  disputed.  Many  clinicians 
state  that  a  general  improvement  follows  it  in  phthisical  patients, 
that  the  appetite  is  improved,  the  cough  and  expectoration  lessened, 
and  that  the  patient  feels  stronger  and  better.  On  the  other  hand, 
others  are  extremely  sceptical  as  to  any  benefits  arising  from  creosote, 
and  regard  it  as  merely  one  of  the  countless  remedies  which  have  been 
recommended  in  this  condition,  and  which,  after  a  shorter  or  longer 
period  of  popularity,  have  passed  into  oblivion. 

It  is  generally  supposed  by  the  advocates  of  the  creosote  treatment 
that  the  remedy  destroys  the  tubercle  bacillus  in  the  lungs  through  its 
antiseptic  properties.  On  the  other  hand,  animals  infected  with 
tubercle  and  treated  with  creosote  die  as  soon  as  controls  which  are 
untreated,  and  the  sputum  of  phthisical  patients  treated  with  creosote 
is  as  virulent  as  that  of  others  not  so  treated.  Besides,  the  adminis- 
tration of  creosote  by  other  ways  than  by  the  mouth  is  said  to  be  very 
much  less  efficacious.  Another  explanation  of  the  creosote  action  is 
that  it  acts  as  an  intestinal  antiseptic  and  prevents  the  secondary 
infection  of  the  bowel;  but  it  has  been  objected  to  this  that  the  other 
intestinal  antiseptics  are  of  little  value  in  tuberculosis.  It  seems 
useless  to  speculate  on  the  method  of  action  until  it  has  been  definitely 
determined  that  creosote  is  of  value  in  phthisis,  and  this  can  be  done 
only  by  careful  statistical  inquiry.  The  medical  profession  seems  to 
have  much  less  faith  in  the  efficacy  of  the  creosote  treatment  than  it 
had  a  few  years  ago,  when  it  was  not  generally  recognized  that  ]n\\- 
monary  tuberculosis  is  curable  by  hygienic  measures  in  a  considerable 
proportion  of  instances. 

VI.  Disinfectants  for  Rooms,  Furniture,  Etc. 

1.    FoRM.\LDEIIYDE. 

Formaldehyde  (HCOH),  the  aldehyde  derived  by  oxidation  from 
methyl  alcohol,  is  a  very  powerful^germicide,  while  it  is  not  ver}'  danger- 


164  SUBSTANCES  ACTING  LOCALLY 

Oils  to  the  higher  animals.  The  aldehyde  is  a  colorless  gas  and  has  been 
used  either  in  solution  in  water  (formaline)  or  as  a  vapor.  As  a  germicide 
it  is  estimated  to  be  equally  efficient  with  corrosive  sublimate,  and  its 
volatility  enables  it  to  penetrate  much  more  rapidly  so  that  it  may  be 
used  for  purposes  for  which  the  latter  is  unsuitable. 

Action. — ^The  vapor  is  very  irritant  when  inhaled,  causing  stinging 
and  prickling  in  the  nose  and  throat,  salivation  ami  tears,  and  bronchial 
irritation  and  catarrh.  In  the  few  cases  of  poisoning  in  man  recorded 
the  symptoms  were  those  of  gastric  irritation  and  consequent  collapse. 
When  swallowed  by  animals  the  watery  solution  produces  nausea  and 
vomiting,  which  are  followed  by  narcosis,  coma,  and  in  the  rabbit  by 
convulsions  and  opisthotonos.  The  respiration  in  the  dog  is  very  greatly 
accelerated  some  time  before  death,  while  in  the  rabbit  this  is  not  so 
marked  or  is  entirely  absent.  The  blood-pressure  is  increased  at  first, 
and  the  heart  is  slow  from  direct  action  on  the  cardiac  muscle.  For- 
maldehyde is  rapidly  absorbed  from  the  alimentary  tract  and  also  by 
the  lungs  but  quickly  disappears  from  the  blood  owing  to  its  oxidation 
and  excretion;  some  formic  acid  is  said  to  be  formed  from  it,  and  for- 
maldehyde has  been  detected  in  the  urine,  the  gastro-intestinal  secretions, 
and  the  expired  air. 

The  powerful  action  of  formaldehyde  on  microbes  and  on  mucous 
membranes  is  believed  by  Loew  to  be  due  to  its  combining  with  the 
amino  groups  in  the  proteins,  and  as  a  matter  of  fact,  a  number  of 
changes  have  been  described  in  the  reaction  of  proteins  exposed  to 
this  gas.  For  example,  egg  albumen  and  serum  to  which  formal- 
dehyde solution  has  been  added  are  not  precipitated  by  heat  and  are 
less  easily  digested  by  ferments,  while  casein  is  not  coagulated  by  the 
rennet  ferment.  Some  of  the  ferments  (pepsin  and  diastase)  are  not 
affected  by  small  amounts  of  formaldehyde,  while  trypsin  and  papain 
lose  their  activity  wholly  or  in  part. 

Preparations. 

Liquor  Fohmaldehydi  (U.  S.  P.,  B.  P.),  formalin,  a  .solution  of  foniialdp- 
hyde  in  wat(>r  coutainiup;  not  less  than  37  per  cent,  of  the  jjas,  wliich  may  be 
obtained  from  it  by  distillation. 

Parafor))},  a  solid  jwlymer  of  fonnakh'liydc,  wliich  is  drcomposod  1)V  hc;it 
and  liberates  tlie  formaldehyde  in  gaseous  form. 

Some  formaldehyde  may  l)c  formed  by  tlie  iiicoiiii^lctc  combusion  of  methyl 
alcohol,  and  several  lamps  have  been  devised  with  this  object  in  view,  but  have 
not  proved  satisfactorj'. 

Uses.-  Formaldehyde  is  too  irritant  to  admit  of  its  use  as  an  anti- 
septic in  medicine  and  surgery,  but  it  has  been  largely  emj)loyed  to 
disinfect  instruments,  furniture,  clothes  and  rooms,  which  caiuiot  be 
sterili'/ed  by  heat.  Dihited  li{|Uor  (4  per  cent.)  may  be  used  for 
some  of  these  ])urposes,  or  the  vapor  may  be  disengaged  by  distilhition 
from  the  li<|Uor  or  1)>'  healing  paraform.  Large  rooms  filled  with  I'or- 
niahh  liydc  xajxir  and  left  for  some  hours  are  foimd  to  be  almost  com- 
pk'tely  sterilized,  so  that  cultures  of  the  ])athogenic  microbes  exposed 


ANTISEPTICS  AND  DISINFECTANTS  KiS 

ill  them  cease  to  grow  even  when  removed  from  the  atmosphere.  Novy 
makes  the  room  to  be  disinfected  as  nearly  air-tight  as  possible  and 
distils  the  formaldehyde  into  it  through  the  key-Iiole  of  the  door. 
He  states  that  the  gas  disengaged  from  150  c.c.  (5  07.)  of  40  per  cent, 
liquor  is  sufficient  for  each  1000  cubic  feet  of  space,  if  the  room  be 
closed  for  ten  hours.  The  odor  of  formaldehyde  may  then  be  removed 
by  sprinkling  ammonia  solution  with  which  it  forms  a  solid  combination. 
The  disinfectant  action  of  formaldehyde  is  increased  by  moderate 
warmth,  and  a  longer  time  must  be  allowed  for  it  to  act  if  the  temperature 
of  the  room  is  below^  50°  F.  Formaldehyde  not  only  destroys  the 
microbes,  but  also  alters  the  toxins  formed  by  them  so  that  they  are  no 
longer  poisonous,  even  in  very  large  quantities. 

Formaldehyde  has  frequently  been  added  to  food,  especially  to 
milk,  as  a  preservative.  Tunnicliffe  and  Rosenheim  found  that  added 
to  milk  in  the  proportion  of  one  to  five  thousand,  formaldehyde  did 
not  seem  to  be  deleterious  to  healthy  children,  but  in  the  case  of  a 
weakly  child  the  protein  waste  was  increased,  and  it  is  certainly  not 
to  be  regarded  as  a  harmless  method  of  preserving  food. 

Formaldehyde  is  not  alone  in  its  germicidal  action,  although  it  is  much 
more  powerful  than  the  other  less  volatile  and  less  active  aldehydes,  such  as 
acetaldehyde. 

Bibliography. 

Loew.     Ein  natiirliches  System  der  Giftwirkungen,  Munchen,  1893,  p.  58. 

Koch.    Amer.  Journ.  of  Physiol.,  vi,  p.  327. 

Fischer.    Journ.  of  Exp.  Med.,  vi,  p.  487. 

Dieudonne.     Arbeit,   a.  d.  Gesundheitsamt.,  xi,  p.  534. 

Anderso?i.     Bulletin  No.  39  of  the  Hygienic  Laboratory,  Washington,  D.  C. 

Pohl.     Arch,  f    exp.  Path.  u.  Pharm.,  xxxi.  p.  295. 

Ermengem  et  Sugg.     Arch,  de  Pharmacodyn.,  i,  p.  141. 

Aronson.    Zts   f.  Hygiene,  1897,  xxv,  p.  168. 

Striiver.     Ibid.,  p.  357. 

McGuigan.    Journ.  Amer.  Med.  Asso.,  1914,  i,  p.  984. 

Benedicenti.    Arch.  f.  [Anat.  u.]  Phys.,  1897,  pp.  210  and  219. 

Novy  and  Waite.     Medical  News,  Ixxii,  p.  641  (1898). 

Bliss  and  Novy.     Journ.  of  Exp.  Med  ,  iv,  p.  47. 

Tunnicliffe  and  Rosenheim.    Journ.  of  Hygiene,  i,  p.  321. 

2.  Sulphur  Dioxide. 

Sulphurous  acid  is  a  powerful  reducing  agent,  as  it  becomes  oxidized 
to  sulphuric  acid,  and  this  renders  it  poisonous  to  protoplasm  in  general, 
quite  apart  from  its  acidity.  Sulphurous  acid  anhydride  is  accordingly 
used  to  a  considerable  extent  to  disinfect  rooms  and  furniture  after 
infectious  diseases;  for  this  purpose  sulphur  is  burned  in  the  room, 
which  ought  to  be  rendered  as  air-tight  as  possible,  and  the  fumes  are 
allowed  to  act  for  several  hours  before  the  room  is  ventilated.  The 
value  of  this  method  of  disinfection  has  been  called  in  question,  but 
there  is  no  doubt  that  sulphurous  acid  gas  is  fairly  germicidal  when  it 
is  applied  along  with  moisture.  It  is  not  capable  of  such  a  wide  applica- 
tion as  formaldehyde,  because  sulphurous  acid  bleaches  many  coloring 


166  SUBSTANCES  ACTING  LOCALLY 

matters,  and  the  procedure  is  open  to  the  objection  that  it  may  lend  a 
sense  of  secnrity  which  is  quite  unwarranted,  and  may  lead  to  the 
iiefilect  of  other  measures.  The  disinfection  to  be  of  any  value  must 
be  thoroughly  carried  out,  and  can  only  be  ajiplied  to  inanimate  objects, 
as  the  fumes  are  fatal  to  the  higher  animals,  even  when  nuich  less  con- 
centrated than  are  necessary  to  destroy  bacteria.  In  order  to  be  of 
service,  at  least  one  volume  of  SO2  ought  to  be  present  in  each  hundred 
volumes  of  air,  and  even  this  concentration  is  insufficient  to  destroy 
the  spores  of  l)acteria.  Novy'  recommends  3-6  pounds  of  sulphur  to  be 
burned  for  each  1000  cubic  feet  of  space;  the  walls  and  floor  should 
be  sprayed  with  water,  and  the  room  must  be  kept  perfectly  closed  for 
at  least  twenty  hours. 

The  chief  symptoms  of  poisoning  with  sulphurous  acid  are  those  of 
irritation  of  the  mucous  membranes,  and  if  the  solution  be  swallowed 
these  may  not  differ  from  those  of  other  irritants. 

In  poisoning  from  the  inhalation  of  the  anhydride,  on  the  other 
hand,  the  symptoms  arise  chiefly  from  the  respiratory  tract.  Even 
in  five  parts  in  10,000  it  acts  as  an  irritant,  causing  sneezing,  coughing 
and  lachrymation,  and  in  somewhat  greater  concentration  it  becomes 
entirely  irrespirable;  still  smaller  quantities  in  the  air  cause  bronchial 
irritation  and  catarrh,  when  inhaled  for  some  time.  Sulphurous  acid 
is  neutralized  and  oxidized  for  the  most  part  to  sulphates  in  the  tissues, 
or  probably  partly  in  the  course  of  absorption. 

3.  Chlorine  and  Bromine. 

Chlorine  and  })romine  resemble  each  other  closely  in  the  effects 
which  they  induce  in  all  forms  of  living  matter.  These  may  be  explained 
in  part  by  their  replacing  hydrogen  in  its  combinations  in  the  proteins 
and  forming  hydrochloric  or  hydrobromic  acid  with  the  hydrogen  set 
free,  in  part  by  their  combining  with  the  hydrogen  of  water  and  thus 
liberating  nascent  oxygen,  which  then  acts  on  the  tissues.  These 
processes  are  believed  to  account  for  the  fact  that  chlorine  is  a  much 
more  powerful  disinfectant  in  moist  air  than  in  dry.  In  the  higher 
organisms  all  of  these  reactions  probably  occur  together. 

Action. — Chlorine  and  bromine  are  general  protoplasm  poisons; 
thus  3  parts  of  chlorine  in  1000  parts  of  moist  air  are  sufficient  to 
destroy  the  spores  of  most  bacteria  in  the  course  of  three  hours,  and 
the  infusoria  and  the  higher  plants  have  been  shown  to  be  equally 
susceptible  to  the  influence  of  the  gas.  Even  smaller  quantities  of 
bromine  are  disinfectant. 

In  the  higher  animals  and  in  man  chlorine  and  bromine  act  as 
irritants,  causing  irritation  and  redness,  and  even  blistering  of  the  skin 
when  applied  to  it  in  solution,  and  eliciting  when  swallowed  intense 
inflammation  and  corrosion  of  the  mouth,  throat,  and  stomach,  with 
collapse  and   all   the  ordinary  efl'ects  of  gastric  irritation.     Air  con- 

^  Novii  and   Waile.      Mc(\ici\\   News,   Ixxii,   p.   fill. 


ANTISEPTICS  AND  DISINFECTANTS  1C.7 

taining  even  a  very  small  proportion  of  chlorine  irritates  the  e\es, 
nose,  larynx  and  the  deeper  respiratory  passages;  bronchitis,  pulmonary 
congestion  and  hjiemorrhages,  coughing  and  pain  in  the  thorax  are 
induced  by  quantities  that  cause  little  or  no  irritation  of  the  mouth 
and  nose.  Lehmann  found  that  one  volume  of  chlorine  or  bromine 
vapor  in  one  million  parts  of  air  causes  some  irritation,  but  no  serious 
results,  but  that  ten  volumes  in  the  same  amount  of  air  inhaled  for 
some  time,  cause  haemorrhage  and  inflammation  of  the  lungs,  severe 
bronchitis,  and  other  similar  effects.  After  fatal  poisoning  from  the 
inhalation  of  bromine,  he  observed  marked  irritation  of  the  gastric 
mucous  membrane,  while  this  symptom  was  absent  after  chlorine. 
Another  point  in  which  bromine  differs  from  chlorine  is  in  its  powerful 
action  on  the  hair,  which  is  rendered  soft  and  gelatinous,  and  eventually 
removed  entirely  by  exposure  for  some  time  to  the  vapor. 

These  symptoms  of  chlorine  and  bromine  poisoning  are  caused  by  their 
local  action  only;  they  are  changed  to  hydrochloric  and  hydrobromic  acids, 
and  these  again  to  chlorides  and  bromides  in  the  course  of  absorption.  Atten- 
tion has  been  drawn  to  a  number  of  cases  in  which  symptoms  arose  in  work- 
men in  chemical  factories  where  chlorine  is  liberated  by  electrolysis,  of  more 
rarely  in  others  where  hydrochloric  acid  is  formed  in  large  quantities.  The 
most  marked  symptom  is  an  affection  of  the  sebaceous  glands,  from  which  the 
condition  receives  its  name  of  chlorine  acne,  but 'this  often  induces  headache, 
sleeplessness,  loss  of  appetite,  and  anemia.  No  satisfactory  explanation  of 
the  symptoms  has  been  given,  nor  is  it  known  whether  the  chlorine  or  some 
unknown  body  is  the  cause  (Lehmann,  Jacquet). 

Preparations. 

Liquor  Chlori  Compositus  (U.  S.  P.),  chlorine  water,  contains  about  4  parts 
of  the  gas  in  1000  parts  of  water.  It  is  a  clear,  greenish  liquid  with  the  suffo- 
cating odor  of  chlorine  and  is  Hable  to  form  hydrochloric  acid,  especially  when 
exposed  to  the  air  and  sunhght.  It  ought  therefore  to  be  freshly  prepared  when 
the  full  strength  is  required. 

Calx  Chlorinata  (U.  S.  P.,  B.  P.),  chlorinated  lime,  bleachmg  powder,  sonie- 
times  erroneously  called  chloride  of  hme,  is  a  mixture  of  calcium  hypochlorite 
(Ca(C10)2),  calcium  chloride  (CaClo),  lime  and  water.  The  hypochlorite  is 
very  unstable  and  gives  off  chlorine  in  air,  and  especially  in  the  presence  of 
an  acid.  Chlorinated  lime  forms  a  white  or  grayish-white  powder,  with  the  odor 
of  chlorine.  It  is  only  partially  soluble  in  water  and  must  contain  not  less  than 
30  per  cent,  of  available  chlorine. 

Liquor  SodcB  Chlorinatce  (U.  S.  P.,  B.  P.),  solution  of  chlorinated  soda,  Labar- 
raque's  solution  or  Javelle's  solution,  is  formed  from  chlorinated  lime  and 
contains  hypochlorite  of  sodium  (NaClO)  and  chloride  of  sodium.  Like  the  cor- 
responding lime  salts,  it  has  the  odor  of  chlorine  and  bleaches  vegetable  colors. 
It  must  contain  at  least  2 .4  per  cent,  by  weight  of  available  chlorine. 

The  chlorine  preparations  are  chiefly  used  to  disinfect  faeces,  urinals 
and  to  a  less  extent  rooms  and  houses;  for  this  purpose  chlormated 
lime  is  the  most  suitable,  especially  when  acid  is  added  to  it  ni  excess. 
The -room  ought  to  be  hermetically  sealed,  and  the  fumes  are  of  no 
value  as  disinfectants  unless  they  are  present  in  such  quantity  as  to 
render  the  air  quite  irrespirable.    They  have  the  disadvantage  that  they 


IfiS  SUBSTAXCES  ACTING  LOCALLY 

l)k"iu-li  most  of  the  colors  used  in  dyeing,  and  fail  to  penetrate  in  sufficient 
quantity  into  the  clothing,  which  they  also  corrode  to  some  extent. 
Cliiorinated  lime  exposed  in  the  sick-room  merely  serves  as  a  deodorant, 
and  has  no  disinfectant  value,  but  has  the  (Hsadvantage  of  giving  a 
false  feeling  of  security  like  other  similar  measures.  Chlorine  seems 
inferior  to  sulphurous  acid  anhydride,  and  still  more  so  to  formaldehyde 
as  a  disinfectant,  not  from  its  being  weaker  in  action,  but  because  it 
is  more  difficult  to  apply  in  sufficient  quantity.  Chlorinated  lime  can, 
however,  l)e  applied  in  urinals  and  closets,  where  both  these  disinfectants 
are  unavailable.  Here  it  acts  again  as  a  deodorant,  while  its  disinfectant 
value  is  smaller. 

Chlorine  water  and  the  solution  of  chlorinated  soda  are  still  occasion- 
ally used  as  disinfectant,  deodorant  solutions  in  the  treatment  of  foul 
sores,  and,  more  rarely,  to  disinfect  the  hands  })efore  operation;  both 
preparations  are  very  irritant,  however.  Chlorine  water  much  diluted 
has  been  used  as  a  gargle,  as  a  vaginal  injection  and  for  other  similar 
purposes. 

Bibliography. 

Binz.    Arch.  f.  exp.  Path.  u.  Pharm.,  xxxiv,  p.  194. 

Lehmann.    Arch.  f.  Hygiene,  vii,  p.  231;   xxxiv,  p.  308;  xh-i,  p.  322. 

richer  u.  Proskauer.    Mittheil.  a.  d.  Gesundhcitsanit,  ii,  p.  228. 

Cash.     Reports  of  Brit.  Local  Gov.  Board,  1886. 

Jacquet.     Semaiue  modicale,  December  31,  1902. 

4.  Other  Disinfectants. 

Many  other  substances  may  be  employed  as  disinfectants  of  urinals, 
latrines,  fieces,  etc.,  the  chief  determining  consideration  being  the 
cost  of  the  material  in  most  cases.  Thus  tar,  or  crude  carbolic  acid 
may  be  used  to  disinfect  hrcal  matter,  and  unslaked  lime  is  applied  to 
bodies  in  epidemics  in  the  hoj)e  of  preventing  the  liberation  of  infectious 
organisms.  The  most  certain  disinfectant,  where  it  is  available,  is  moist 
heat,  which  is  generally  used  to  disinfect  clothes  and  bedding  which 
have  been  in  contact  with  infected  persons. 


PART  II. 

SUBSTANCES  CHARACTERIZED  CHIEFLY  BY 
THEIR  ACTION  AFTER  ABSORPTION. 


I.     NARCOTICS  OF  THE  METHANE  SERIES. 
ALCOHOL-CHLOROFORM  GROUP. 

A  LARGE  number  of  the  simpler  methane  compounds  of  the  open-chain 
series  cause  depression  of  the  central  nervous  system,  more  especially 
of  the  cerebrum,  and  some  of  them  are  perhaps  the  most  extensively 
used  of  all  drugs,  for  among  them  are  the  universally  used  surgical 
anaesthetics,  the  soporifics,  and  alcohol.  The  general  action  of  all  of 
these  is  similar  in  character  and  consists  of  a  first  stage  of  imperfect 
consciousness  and  confused  ideas,  followed  by  one  of  wild  excitement, 
and  eventually  by  complete  unconsciousness,  w^hich  may  terminate  in 
death.  The  second  stage  is  much  more  marked  after  some  of  the 
series  than  after  others,  and  is  often  entirely  absent.  It  has  given 
rise  to  the  theory  that  these  drugs  stimulate  the  nerve  cells  before 
paralyzing  them,  but  an  alternative  explanation  is  that  the  functions 
of  control  and  inhibition  are  lessened,  and  the  centres  of  motion  are 
thus  left  free  and  act  more  strongly  than  normally.  This  question 
has  been  most  discussed  in  regard  to  alcohol,  and  will  receive  greater 
attention  under  that  heading. 

The  action  on  the  central  nervous  system  is  elicited  by  comparatively 
small  quantities  of  these  drugs,  but  other  forms  of  living  matter  are  also 
affected  by  them  in  somewhat  greater  concentration,  and  their  action 
may  in  short  be  considered  as  coextensive  with  life,  though  in  man  and 
the  higher  animals  the  symptoms  from  the  brain  predominate. 

The  different  members  of  the  group  vary  greatly  in  their  chemical 
nffinities  and  in  their  tendency  to  enter  into  chemical  combinations,  and 
00  relation  can  be  found  between  their  narcotic  action  and  the  presence 
ef  any  one  radical.  This  suggests  that  their  effects  depend  on  the  prop- 
arties  of  the  molecule  as  a  whole,  and  not  on  a  chemical  combination 
being  formed  with  any  constituent  of  the  tissues.  A  very  interesting 
view  has  recently  been  suggested  by  Meyer  and  Overton,  who  attribute 
the  common  action  of  these  narcotics  to  a  common  physical  character. 
They  point  out  that  practically  all  of  them  are  more  soluble  in  oils  an<l 
lipoids  than  in  water  and  that  when  one  of  these  drugs  in  watery  solution 
meets  an  oil  or  lipoid  it  passes  from  the  water  to  the  oil  and  remains 
dissolved  in  it.  The  same  process  occurs  when  these  drugs  are  carried 
in  the  blood;  they  tend  to  leave  the  watery  plasma  and  to  accunnilate 

(169) 


170  SUBSTANCES  ACTING  AFTER  ABSORPTION 

in  tlic  lipoids  of  the  body,  and  as  the  nerve  cells  are  richest  in  lipoids, 
the  narcotics  accunuilate  in  the  brain.  This  is  a  purely  physical  process 
and  the  amount  of  the  drug  taken  up  from  the  blood  is  determined 
by  its  relative  solubility  in  the  lipoids  and  in  the  blood  (coefficient  of 
partition  between  oils  and  water).  According  to  Meyer's  view,  the 
presence  of  the  drugs  in  the  lipoids  renders  these  more  fluid  and  thus 
changes  their  relations  to  the  other  constituents  of  the  cells;  this  derange- 
ment of  their  normal  condition  impairs  the  function  of  these  cells  and 
lessens  their  activity,  that  is,  causes  narcosis.  This  very  attractive 
theory  has  been  supported  by  a  number  of  experiments  and  serves  to 
explain  a  large  number  of  observations;  the  accordance  of  the  coefficient 
of  partition  and  the  narcotic  power  is  seen  to  be  very  close,  especially 
when  members  of  a  homologous  series  are  compared;  for  example, 
the  narcotic  action  of  the  simple  alcohols  rises  from  methyl  and  ethyl 
alcohol  through  propyl  and  butyl  alcohol  to  amyl  alcohol,  which  is 
the  most  powerful  of  the  series,  and  the  tendency  of  the  alcohols  to 
pass  from  water  into  oil  rises  similarly.  On  the  other  hand  when  the 
hydroxyl  groups  of  the  alcohols  are  increased,  as  in  the  series  ethyl 
alcohol,  glycol  and  glycerine,  the  partition  coefficient  between  oil  and 
water  falls,  and  the  narcotit  action  declines. 

The  experiments  of  Meyer,  Overton  and  their  followers  suffice 
to  show  that  these  physical  properties  are  factors  in  the  narcotic 
action.  But  these  are  not  the  only  determining  influences.  For  when 
the  relative  narcotic  action  of  less  nearly  related  bodies  are  compared, 
the  dependence  on  the  partition  coefficient  is  less  exact;  for  example, 
the  relative  coefficients  of  partition  of  alcohol,  chloral  and  acetone  are 
approximately  1  :2  :G,  but  their  narcotic  action  is  1  :  16  : 1.  There  is 
evidently  some  unknown  factor  which  plays  an  important  role  in 
determining  the  action,  besides  the  solubility  coefficient.  It  seems 
likely  that  the  distribution  in  the  tissues,  and  the  concentration  of  the 
narcotics  in  the  central  nervous  system  is  largely  determined  by  the 
relative  solubility  in  water  and  lipoids,  but  that  after  the  narcotics 
have  penetrated  into  the  brain  cell  the  efl'ects  depend  on  some  further 
quality  which  is  still  unknown.^ 

Various  suggestions  have  been  made  of  late  years  as  to  the  nature  of  narcosis. 
The  old  view  that  it  was  due  to  changes  in  the  blood  supply  and  to  autemia  of 
the  brain  lias  long  been  abandoned,  since  it  was  shown  that  the  brain  of  a  frog 
in  which  the  blood  was  replaced  by  saline  solution,  could  still  be  anaesthetized. 
There  is  no  question  that  the  action  of  the  narcotics  is  a  direct  one  on  the 
nervous  structures,  and  that  the  changes  in  the  brain  circulation,  which  arc 
similar  to  those  in  normal  sleep,  are  the  result  and  not  the  cause  of  the  narcotic 
action. 

Verworn  believes  that  narcosis  arises  from  the  arrest  of  the  oxidations  in  the 
cells,  and  in  many  instances  a  lessened  oxidation  has  been  shown  to  be  present 

'  A  suggestion  has  been  made  that  these  narcotics  may  act  by  changing  the  surface 
tension  of  the  cell  contents  and  thus  disorganizing  the  life  processes.  It  seems  clear  that 
this  will  not  serve  to  explain  every  case,  however,  and  in  fact  is  less  satisfactory  than  the 
Mcyer-Overtou  view.  It  appears  unlikely  that  any  one  physical  property  determines 
the  action  of  these  bodies,  though  the  sum-total  of  the  physical  properties  may  suffice 
to  do  so. 


NARCOTICS  OF  THE  METHANE  SERIES  171 

during  narcosis.  But  on  the  other  hand  narcosis  may  he  induced  in  cells  which 
live  in  the  absence  of  oxygen  (intestinal  parasites),  and  cases  arc  known  in  which 
narcosis  is  not  accompanied  l)y  lessened  oxidation.  The  decrease  in  oxidation 
which  is  seen  in  narcosis  may  thus  be  the  n^sult  and  not  the  cause  of  the  essen- 
tial action. 

Lillie  holds  that  the  essential  feature  of  narcosis  is  the  diniinislicd  permea- 
bility of  the  cell  membranes  by  ions,  which  can  no  longer  penetrate  as  is  necessary 
for  activity.  This  diminished  permeability  may  be  the  result  of  changes  in  the 
lipoids  such  as  are  demanded  in  the  Meyer-Overton  theory. 

Certain  features  of  the  chemical  constitution  of  the  members  of  this  group 
have  already  been  mentioned.  Thus  it  is  found  that,  as  a  general  rule,  the  higher 
members  of  a  series  are  more  strongly  depressant  than  the  lower,  provided  they 
are  sufficiently  soluble  in  water  to  be  taken  up  by  the  blood,  and  a  correspond- 
ing increase  in  the  partition  coefficient  is  presented.  The  increase  in  hydroxyl 
groups  which  augments  the  solubility  in  water  has  the  opposite  effect,  lowering 
the  narcotic  action;  but  if  the  hydroxyl  is  substituted  by  chlorine  the  narcotic 
action  returns;  for  example,  propionic  alcohol  (C3H7OH)  is  narcotic  but  gly- 
cerin (C3H5(OH)3)  is  indifferent,  while  trichlorhydrin  (C3H5CI3)  is  less  soluble 
in  water  and  again  acts  as  a  narcotic. 

The  presence  of  the  carboxyl  group  (COOH)  generally  prevents  any  nar- 
cotic action,  probably  because  the  acids  formed  circulate  as  salts  and  these  can- 
not penetrate  the  cells  in  sufficient  concentration.  Butyric  acid  is  said  to  have 
some  narcotic  effect,  but  this  may  arise  from  the  presence  of  esters.  When  hy- 
drogen atoms  of  these  acids  are  replaced  by  chlorine  or  bromine,  they  acquire 
a  much  stronger  action;  thus  acetic  acid  is  practically  devoid  of  narcotic  action, 
while  some  of  the  chloracetic  and  bromacetic  acids  are  narcotic.  But  their  effects 
on  the  other  organs  of  the  body  preclude  their  use  in  therapeutics. 

Tliis  augmented  action  through  the  substitution  of  halogens  for  hydrogen  is 
seen  in  many  other  instances;  for  example,  methane  (CH4)  is  practically  not 
depressant,  but  if  one,  two,  or  three  of  the  hydrogen  atoms  in  the  molecule 
be  substituted  by  chlorine,  forming  CH3Cl,CH2Cl2,  and  CHCI3,  the  narcotic 
power  increases  with  each  CI  added. 

This  increased  activity  of  the  halogen  compounds  is  not  due  to  any  action 
of  chlorine  or  bromine  on  the  nerve  cells,  for  these  elements  are  not  freed  from 
their  compounds,  which  act  as  unchanged  molecules;  for  example,  chlorine  is 
not  Hberated  from  chloroform  in  the  tissues,  but  the  whole  molecule  CHCI3 
acts  as  an  anaesthetic,  while  methane  has  no  such  action. 

The  chlorine  md  bromine  derivatives  of  methane  are  not  only  more  power- 
ful drugs,  but  also  more  powerful  poisons  than  the  ordinary  compounds;  much 
'less  chloroform  is  required  to  anaesthetize  than  methane,  but  much  less  is 
required  to  kill.  In  addition,  these  compounds,  especially  those  contain- 
ing chlorine,  seem  to  have  a  more  powerful  action  on  the  heart  and  circulation 
and  on  the  metabolism  than  the  others.  In  other  words,  the  clilorine  bodies 
have  a  less  specific  action  on  the  nerve  cells  and  thus  involve  a  larger  number  of 
tissues  in  their  effects.     (See  Chloroform.) 

Many  methane  compounds  are  not  narcotic  because  they  contain  more  active 
radicles.  Thus  ethane  (CjHe)  is  a  member  of  the  narcotic  series,  but  ethyl 
nitrite  (C2H2O  —  NO)  cannot  be  classed  with  it,  because  the  —  0  —  NO  group 
has  a  very  powerful  and  entirely  different  effect;  very  small  quantities  of 
ethyl  nitrite  are  required  to  produce  the  nitrite  effect,  so  that  the  depressant 
action  is  pushed  into  the  background.  Members  of  the  methane  series  often 
lose  their  depressant  action  when  combined  with  nitrogen  so  as  to  form  sub- 
stituted ammonia.  Thus  trimethylamine  (N(CH3)3)  has  no  depressant  action, 
although  each  of  the  methyl  radicles  alone  would  possess  it.  Again,  the  sub- 
stitution of  a  member  of  the  aromatic  series  for  one  of  the  fatty  substances 
sometimes  changes  the  action  from  that  characteristic  of  the  alcohol-chloro- 
form group  to  that  of  the  benzol  series.  For  example,  ether  (CjUs—  0  — 
C2H5)  is  one  of  the  most  valuable  anaesthetics,  but  if  one  ethyl  radicle  be  sub- 


172  SUBSTANCES  ACTIXC   AFTER  ABSORPTION 

.stitulcd  by  phenyl  (Colls —  O  —  Colls),  it  loses  this  property  entirely.  Others, 
however,  retain  their  depressant  action,  as,  for  example,  acetophenone  (Cells — 
CO  — CH3). 

While  the  members  of  this  group  resemble  each  other  closely  in 
their  effects  on  the  central  nervous  system,  they  are  used  for  very 
different  purposes  in  theraj^eutics  and  may  therefore  be  discussed  in 
three  subijroups:  1,  alcohol;  2,  general  ana'sthetics,  and  3,  soporifics 
or  hypnotics.  It  must  be  recognized,  however,  that  there  is  no  hard 
and  fast  line  dividing  these  subgroups;  for  the  anaesthetics,  chloroform 
and  ether,  ma\-  be  used  in  small  quantities  to  produce  rest  and  sleep,  and 
would  then,  strictly  speaking,  be  soporifics;  while,  on  the  other  hand, 
chloral  and  sulphonal,  which  are  generally  used  as  hyi)notics,  give  rise 
to  complete  aniesthesia  when  administered  in  large  quantities. 


Bibliography. 

Meyer.    Arch.  f.  exp.  Path.  u.  Pharm.,  xlii,  p.  109;    xlvi,  p.  338. 

Overton.     Studien  iiber  die  Narcose,  Jena,   1901. 

Gottlieb.     Ergebnisse  der  Physiol.,  i,  2,  p.  66G. 

Mayer.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxi,  p.  97,  119. 

Pohl.     Ibid.,  xxiv,  p.  142. 

Marshall  and  Heath.     Journ.  of  Physiol.,  xxii,  p.  38. 

Kionka.     Arch,  internat.  de  Pharmacodyn.,  vii,  p.  475. 

Lillie.     Amer.  Journ.  of  Physiol,  1912,  xxix,  p.  372. 

Fuhner.     Ztschr.  f.  Biol.,   1912,  Ivii,  p.  465. 

Winterstein.     Biochcni.  Zeitschr.,  li,  p.  143. 

Loewe.     Ibid.,  Ivii,  p.  161. 

1.  Alcohol. 

Ethyl  alcohol  (CHijCTI^OTI)  has  been  known  in  an  impure  form 
since  the  earliest  times,  aiid  as  far  back  as  the  history  of  medicine 
extends,  has  been  used  as  a  drug.  Its  medicinal  reputation  has  under- 
gone many  fluctuations,  by  many  held  to  be  a  panacea,  by  others  it  has 
been  considered  of  importance  only  as  a  poison. 

Alcoholic  licjuors  are  generally  prepared  by  the  fermentation  of 
sugars,  which  either  exist  preformed  in  the  fruits,  or  are  derived  from 
starch  by  a  })reliminary  ferment  action.  The  simple  liquors  (wines 
and  beers)  generally  contain  only  a  low  i)ercentage  of  alcohol  (2-20 
per  cent.),  and  the  stronger  preparations  (spirits)  are  prepared  from 
them  by  distillation,  which  raises  the  percentage  to  ;>()  00  per  cent, 
and  at  the  same  time  removes  the  non-volatile  constituents.  Spirits 
and  liquors  are  not,  however,  simple  mixtures  of  alcohol  and  water  but 
contain  many  other  volatile  substances,  the  character  of  which  is  little 
known,  and  which  are  called  a-nanthic  ethers.  Some  of  them  have 
been  shown  to  be  higher  members  of  the  alcoholicseries,  while  others 
would  seem  to  be  of  entirely  diil'erent  constitution. 

Action. — The  value  of  alcohol  in  medicine  depends  upon  three  chief 
points:  1,  its  irritant  local  action;  2,  its  action  on  the  central  nervous 
svstem,  and  '.i,  its  value  as  a  food. 


ALCOHOL  173 

The  irritant  action  is  not  so  marked  as  that  of  many  other  suhstances, 
but  is  of  much  p;reater  importance,  owinji;  to  the  habitual  use  of  this 
drug.  It  is  probably  due  to  the  partial  precipitation  of. the  proteins 
of  the  cells,  and  is  shown  by  the  results  of  its  application  to  tlie  skin, 
to  wounds,  and  to  the  mucous  membranes.  Applied  to  the  skin  in 
sufficient  concentration  (e.  g.,  GO-90  per  cent.),  it  produces  redness, 
itching  and  a  feeling  of  heat  like  other  volatile  and  irritant  substances, 
such  as  the  volatile  oils.  Alcohol  is,  however,  much  less  irritant  and 
at  the  same  time  more  volatile  than  these,  so  that  unless  its  evaporation 
is  prevented,  it  may  produce  a  sensation  of  cold  and  have  little  or  no 
irritant  action;  this  is  especially  the  case  when  dilute  alcohol  is  used, 
no  very  distinct  appearances  of  irritation  of  the  skin  being  produced  by 
solutions  under  40-50  per  cent.  In  ulcers  and  other  unprotected 
surfaces,  the  irritant  action  is  much  greater  and  its  application  is 
attended  by  pain  and  smarting;  the  precipitation  of  the  proteins  lends 
alcohol  an  astringent  action  in  certain  concentrations,  but  if  it  pene- 
trate deeper  it  may  destroy  the  cells  and  it  then  becomes  a  corrosive 
until  it  is  diluted  by  the  fluids. 

Its  effects  on  mucous  membranes  are  similar  to  those  on  wounds. 
In  the  mouth  strong  alcohol  produces  a  burning,  unpleasant  sensation 
which  passes  to  the  throat  and  stomach  when  it  is  swallowed,  and  if 
the  concentrated  vapor  be  inhaled,  it  causes  irritation  and  reflex 
closure  of  the  glottis.  The  efi^ects  of  alcohol  on  the  digestive  functions 
are  so  important  that  they  will  receive  further  attention  (p.  179). 

The  action  of  alcohol  on  the  Nervous  Centres  difters  a  good  deal  in 
individuals.  In  small  quantities  it  generally  produces  a  feeling  of 
well-being  and  good-fellowship,  along  with  increased  confidence  in  the 
powers,  mental  and  physical,  of  the  subject  of  the  experiment.  Larger 
quantities  are  followed  by  a  certain  amount  of  excitement,  marked  by 
laughter,  loquacity,  and  gesticulation.  The  face  becomes  flushed  and 
hot,  the  eyes  brighter  and  livelier,  the  pulse  is  accelerated.  Even  at 
this  stage  self-control  is  partially  lost  and  the  will  power  is  weakened. 
The  speech  may  be  brilliant,  but  it  often  betrays  the  speaker;  the 
movements  are  more  lively,  but  they  are  often  undignified.  The  loss 
of  self-control  is  often  indicated  further  by  furious  outbursts  of  anger 
and  unreasonableness,  or  by  the  indulgence  in  maudlin  sentimentality 
and  sensual  fancies.  The  sense  of  responsibility  and  the  power  of 
discrimination  between  the  trivial  and  the  important  are  lost,  and 
the  individual  has  no  regard  for  the  feelings  of  others,  or  the  ordinary 
conventions  of  life.  If  the  bout  be  further  continued,  the  movements 
become  uncertain,  the  speech  becomes  difficult  and  stammering,  the 
walk  becomes  a  stagger,  and  a  torpid  slumber  follows.  Often  nausea 
and  vomiting  set  in,  although  these  are  entirely  absent  in  some  cases. 
On  awakening  from  slumber,  very  great  depression  is  generally  sufTered 
from,  together  with  nausea  and  vomiting,  and  want  of  appetite,  which 
may  last  for  several  days  and  is  associated  with  all  the  symptoms  ot 
acute  gastric  catarrh. 

Very  large  quantities  of  alcohol  lead  to  a  deep,  torpid  sleep,  which 


174  SUBSTANCES  ACTING  AFTER  ABSORPTION 

eventually  passes  into  total  unconsciousness,  resembling  the  condition 
in  chloroform  anaesthesia;  the  respiration  becomes  stertorous  and  slow, 
and  the  face,,  which  has  hitherto  been  flushed,  becomes  pale  or  cyanotic. 
This  condition  may  last  for  several  hours  and  end  in  death  from  failure 
of  the  respiration,  but  in  other  cases  the  anaesthesia  becomes  less  deep 
and  after  a  very  prolonged  sleep  the  patient  recovers.  When  the  stage 
of  anaesthesia  is  reached,  it  lasts  ^•ery  much  longer  than  that  produced 
by  chloroform  and  ether.  It  is  said  that  persons  rarely  or  never  recover 
if  unconsciousness  lasts  longer  than  10-12  hours  after  the  drinking  bout. 

The  effects  of  alcohol  vary  greatly,  however,  in  different  individuals 
and  in  the  same  individual  at  different  times.  One  person  is  rendered 
sentimental,  another  bellicose,  while  in  a  third  there  may  be  no  appear- 
ance of  excitement,  the  first  distinct  symi)tom  being  profound  slumber. 
When  drinking  is  indulged  in  in  company,  the  excitement  stage  is  a  very 
common  phenomenon,  but  if  alcohol  is  taken  without  the  exhilarating 
accompaniments  of  bright  lights  and  exciting  companionship,  it  is  much 
less  frequently  seen,  and  the  question  has  therefore  arisen  how  far  the 
environment  produces  the  excitement  in  alcoholic  intoxication. 

It  may  be  stated  at  once  that  there  exist  two  distinct  views  as  to  the 
action  oi  alcohol  on  the  central  nervous  system:  the  one  stoutly  upheld 
by  Binz  and  his  pupils,  that  alcohol  first  stimulates  and  then  depresses 
the  nerve  cells;  the  other  championed  by  Schmiedeberg,  Bunge  and 
their  followers,  that  it  depresses  the  central  nervous  system  from  the 
beginning.  The  symptoms  of  excitement  require  no  explanation  on 
the  first  theory,  which  is  rather  to  be  looked  on  as  the  natural  expression 
of  the  facts  observed.  On  the  other  hand,  Schmiedeberg  explains 
them  as  not  due  to  true  stimulation  of  the  motor  areas,  but  as  the 
result  of  these  areas  being  freed  from  control  by  the  weakening  of  the 
highest  functions  of  the  brain— the  will  and  self-restraint.  Even  the 
smallest  quantities  of  alcohol  tend  to  lessen  the  activity  of  the  brain, 
the  drug  appearing  to  act  most  strongly,  and  therefore  in  the  smallest 
quantities,  on  the  most  recently  acquired  faculties,  to  annihilate  those 
qualities  that  have  been  built  up  through  education  and  experience, 
the  power  of  self-control  and  the  sense  of  responsibility. 

The  question  is  a  most  difhcult  one  to  decide,  for  on  the  one  hand  it 
has  been  shown  that  the  simjjlest  movement  is  the  result  of  a  combi- 
nation of  motor  and  inhibitory  impulses  from  the  brain,  while  on  the 
other  hand  the  measurement  of  the  relative  strength  of  these  impulses 
is  one  of  the  most  difficult  problems  of  biology.  The  advocates  of  the 
stimulant  action  point  to  the  confidence  in  their  own  i)owcrs  exhibited 
by  intoxicated  persons,  to  the  brilliancy  of  the  after-dinner  speech,  and 
to  the  excitement  stage  as  evidences  of  the  increased  activity  of  the 
brain.  But  their  opponents  question  whether  the  confidence  is  accom- 
l)anie(l  by  any  really  increased  i)hysical  strength,  and  i)oint  out  that 
the  brilliancy  of  speech  may  be  due  to  the  environment  and  to  the 
speaker  having  lost  his  habitual  shyness  and  nervousness,  and  that  the 
excitement  is  generally-  absent  when  the  associations  are  different,  or 
degenerates  into  a  form  which  more  distinctly  resembles  depression. 


ALCOHOL  175 

More  definite  evidence  for  or  against  the  stimulant  action  of  alcohol 
has  therefore  been  sought  by  comparing  the  amount  of  work  which 
can  be  done  with  and  without  it;  and  an  a])parent  confirmation  of 
Bunge's  view  has  been  found  in  the  results  of  the  use  of  alcohol  by 
troops  on  the  march,  for  repeated  experience  has  shown  that  those 
regiments  which  were  not  supplied  with  alcohol  marched  farther  and 
were  in  better  condition  at  the  end  of  the  day  than  others  to  which  it 
had  been  given.  The  experiments  of  Durig  in  climbing  lead' to  the 
same  result,  the  total  work  done  being  smaller  under  alcohol  and  the 
expenditure  of  energy  greater.  Forms  of  work  requiring  larger  drafts 
upon  the  intelligence  than  the  marching  of  soldiers  are  also  performed 
less  correctly  with  alcohol  than  without  it;  thus  typesetters  can  do 
more  work  and.  make  fewer  errors  when  they  abstain  from  its  use. 

The  capacity  for  work  depends  not  so  much  upon  the  actual  strength 
of  the  muscles  as  upon  the  condition  of  the  brain,  and  these  experi- 
ments are  therefore  generally  quoted  as  evidence  of  the  depressant 
action  of  alcohol.  Their  results  are  not  incompatible  with  the  \iew 
that  alcohol  primarily  stimulates  the  nerve  cells,  however,  for  Binz 
and  his  followers  allow  that  the  stimulation  is  transient  and  is  followed 
by  depression,  and  if  a  sufficient  time  elapse  after  the  alcohol  is  taken, 
the  stage  of  depression  is  elicited  and  the  total  work  may  thus  be  reduced. 

x\ttempts  have  been  made  to  measure  the  work  done  under  alcohol, 
l)y  recording  with  the  ergograph  the  work  of  which  a  muscle  is  capable 
before  it  is  completely  fatigued.  The  best  investigations  are  those  of 
Rivers,  who  took  the  precaution  of  disguising  the  alcohol  with  flavors 
so  that  the  subject  of  the  experiment  was  unaware  when  alcohol  was 
given.  His  results  indicate  that  small  quantities  of  alcohol  (5-20  c.c, 
corresponding  to  about  a  tablespoonful  and  a  wineglassful  of  spirits) 
have  very  little  effect  on  muscular  work  measured  in  this  way.  When 
larger  amounts  of  alcohol  were  taken,  Rivers  found  that  an  exceptional 
amount  of  work  could  be  performed  before  fatigue  appeared,  but  he 
considers  this  due  to  the  fact  that  the  alcohol  could  no  longer  be  con- 
cealed and  the  subject  was  now  influenced  by  suggestion. 

In  measurements  of  intellectual  work,  the  factor  of  suggestion  is  of  still 
greater  moment  and  the  observations  of  Kraepelin  lose  much  of  their 
importance  from  the  fact  that  the  subjects  knew  when  alcohol  had  been 
given  them.  He  concluded  that  the  receptive  and  intellectual  powers  were 
weakened  by  very  small  quantities  of  alcohol,  while  the  motor  functions 
seemed  to  be  facilitated  by  small,  and  retarded  by  large  quantities. 
For  example,  a  person  under  even  a  small  dose  of  alcohol  makes  more 
errors  than  usual  in  adding  a  row  of  figures  and  in  reading  a  series 
of  unconnected  syllables,  and  apparently  recognizes  letters  and  Avords 
somewhat  more  slowly.  It  is  interesting  to  find  that  the  subject  of 
the  experiment  is  quite  unaware  of  the  inferiority  of  his  work  and  is 
often  persuaded  that  it  is  unusually  good.  It  must  be  added  that 
this  depressant  effect  is  not  equally  elicited  in  different  individuals, 
and  even  100  c.c.  of  alcohol  (corresponding  to  about  half  a  pint  of 
spirits)  fails  to  induce  it  in  some  persons.     Kraepelin's  latest  investi- 


176  SUBSTANCES  ACTING  AFTER  ABSORPTION 

gations  tend  to  show  that  this  effect  of  alcohol  lasts  much  longer  than 
is  generally  recognized,  the  mental  equilibrium  being  reinstated  only 
12-24  hours  after  even  very  moderate  indulgence  in  alcohol.  He 
leans  to  the  view  that  alcohol  weakens  and  paralyzes  some  parts  of 
the  brain,  while  primarily  stimulating  others,  but  brings  forward  no 
new  evidence  that  this  stimulation  is  not  fictitious  and  really  due  to 
the  removal  of  the  barriers  of  self-restraint  by  the  paralysis  of  higher 
areas.  Most  other  psychological  experiments  give  similar  results,  and  no 
unequivocal  evidence  of  the  initial  stimulant  action  on  the  brain  has 
yet  been  adduced,  for  each  new  feature  may  be  interpreted  as  really  due 
to  the  depression  of  controlling  or  inhibitory  functions.  Of  course, 
there  is  no  absolutely  convincing  proof  that  no  stimulation  of  the  motor 
areas  occurs,  and  no  physiological  proof  of  the  existence  even  of  control- 
ling areas  can  be  adduced,  much  less  of  their  paralysis  by  alcohol.  On 
the  other  hand,  the  effects  of  alcohol  on  cerebral  activity  are  very 
different  from  those  of  caffeine,  which  definitely  increases  both  mus- 
cular and  mental  efficiency,  and  thus  is  the  typical  brain  stimulant. 
Exaggerated  importance  has  been  attached  to  this  question  from  the 
idea  that  it  is  more  justifiable  to  employ  a  "stimulant"  than  a  "de- 
pressant," but  in  therapeutics  this  is  not  a  valid  argument  for  or 
against  the  use  of  alcohol. 

In  the  lower  parts  of  the  central  nervous  system  the  evidences  of 
primary  depression  are  less  open  to  question.  For  example,  the  coor- 
dination of  the  movements  suffers  at  an  early  stage  in  alcohol  drink- 
ing, long  before  the  generally  recognized  forms  of  lack  of  co5rdination, 
such  as  indistinct  speech  and  staggering,  appear.  In  the  spinal  cord 
alcohol  causes  a  depression  of  the  reflex  irritability,  which  passes  into 
complete  paralysis  some  time  before  the  respiration  ceases. 

Alcohol  has  been  found  to  cause  a  prolonged  secretion  of  the  cerebro- 
spinal fluid  and  to  raise  the  pressure  in  the  subarachnoid  space,  and 
it  has  been  suggested  that  this  may  account  in  part  for  its  after  effects 
which  have  generally  been  attributed  to  gastric  disturbance. 

Acute  alcoliolic  intoxication  leads  to  very  distinct  alterations  in  the  liisto- 
logical  ajjpearauce  of  the  cells  of  tlic  central  nervous  system,  wliich  have  been 
(l(>scril)e(l  by  Dehio,  Stewart,  and  others.  The  chief  cliange  noted  by  tlieni 
consists  in  rc))lacement  of  the  chromatin  network  by  tine  j^ranules,  which  in 
turn  seem  to  become  dissolved  in  the  general  cytoplasm.  Staining  reagents, 
therefore,  give  rise  to  a  diffused  coloration  of  the  cell  rather  than  to  localized 
masses  of  color,  such  as  are  seen  in  the  normal  cell. 

Tlie  medulla  oblongata  is  the  last  part  of  the  central  nervous  system 
to  be  acted  on  by  alcohol,  or  at  any  rate  to  undergo  complete  paralysis. 
The  Respiratory  and  Circulatory  Centres  ])reserve  their  functions  long 
after  the  occurrence  of  complete  unconsciousness  and  the  disappearance 
of  tlu>  ordinary  reflexes.  The  same  question  has  been  raised  in  regard 
to  the  respiratory  centre,  as  has  been  already  discussed  in  the  con- 
sideration of  the  brain,  and  the  same  two  op])osing  views  have  been 
U|)Ii<ld.     These  are  of  greater  importance  as  regards  the  respiratory 


ALCOHOL  177 

centre,  because  the  advocates  of  the  stimulation  theory  advise  the  use 
of  alcohol  in  conditions  of  the  respiration  in  which  it  is  directly  contra- 
indicated  if  the  other  view  be  the  correct  one.  The  question  here  is 
apparently  much  more  simple,  because  the  activity  of  the  respiratory 
centre  can  be  estimated  directly  by  measuring  the  number  of  the 
respirations  and  the  amount  of  air  inhaled  during  each;  but  a  large 
number  of  such  experiments  have  been  performed  with  very  varying 
results.  If  the  number  of  the  respirations  be  counted  in  a  person  in 
the  excitement  stage  of  alcoholic  intoxication,  it  is  often  found  to  be 
much  greater  than  normally,  but  this  may  be  due  to  the  muscular 
movements  and  need  not  indicate  an}^  direct  action  of  the  drug  on  the 
medullary  centre.  And,  of  course,  this  excitement  stage  is  not  elicited 
in  therapeutics,  and  the  value  of  alcohol  as  a  respiratory  stimulant 
must  therefore  be  estimated  in  cases  in  which  no  such  excitement  is 
caused.  A  number  of  such  estimations  have  been  made  in  man  and 
animals,  and  on  the  whole  the  evidence  shows  that  in  man  even  when 
no  excitement  is  produced  and  in  some  instances  even  when  sleep 
follows,  the  amount  of  air  inhaled  is  larger  than  before  the  drug  was 
administered  (Jaksch,  Zuntz  and  Berdez,  Geppert,  Weissenfeld,  Wen- 
delstadt);  the  increase  is  generally  more  evident  when  alcohol  is  taken 
during  fatigue  and  exhaustion  than  in  ordinary  conditions.  This 
may  not  indicate  a  direct  stimulation  of  the  respiratory  centre,  how- 
ever, for  the  increase  is  often  not  greater  than  that  following  an  ordinary 
meal,  and  may  therefore  be  attributed  to  the  respiratory  centre  being 
indirectly  affected  by  the  activity  of  the  stomach  and  intestine.  The 
actual  excitability  of  the  respiratory  centre  may  be  measured  by  its 
response  to  the  inhalation  of  carbon  dioxide,  and  Loewy's  observations 
by  this  method  do  not  lend  support  to  the  view  that  the  excitability 
is  augmented.  There  is  therefore  no  sufficient  evidence  that  the  respira- 
tory centre  is  directly  stimulated  in  man,  and  the  increase  in  the  amount 
of  air  inhaled  may  be  due  to  the  peripheral  action  of  alcohol. 

In  the  dog,  no  acceleration  of  the  respiration  occurs  after  alcohol,  while 
in  the  rabbit,  on  the  other  hand,  the  respiration  is  much  accelerated,  and  the 
amount  of  air  inhaled  shows  a  corresponding  increase.  It  is  still  a  matter  of 
dispute,  however,  whether  this  arises  from  direct  action  on  the  centre  or  from 
the  irritation  of  the  stomach,  the  dilatation  of  the  vessels,  and  other  peripheral 
effects  (Jacquet,  Wilmanns,  Singer). 

In  short,  there  is  no  unequivocal  evidence  that  the  increase  in  the  resi)i- 
ration  under  alcohol  in  health  is  due  to  direct  stimulation  of  the  respiratory 
centre,  while  on  the  other  hand,  no  depression  of  the  activity  of  this  centre 
occurs  except  at  a  late  stage  of  alcohol  poisoning.  Alcohol  is  often  said  to  slow 
the  respiration  in  fever  patients  and  to  stimulate  it  in  cases  of  shock.  In  the 
first  case  the  improvement  (when  present  at  all)  is  probably  due  to  the  alcohol 
lessening  the  excitement  through  its  narcotic  action,  while  its  value  in  shock  is 
disputed  by  most  careful  observers. 

From  a  practical  point  of  view  the  question  is  of  little  importance, 
for  the  changes  in  the  respiration  induced  by  alcohol  are  too  sinall  and 
too  inconstant  to  play  any  part  in  the  treatment  of  respiratory  disorders. 

12 


178 


SUBSTANCES  ACTISG  AFTER  ABSORPTION 


Circulation. — The  pulse  is  accelerated  during  the  excitement  of 
alcoholic  intoxication,  but  this  is  due  to  the  increased  muscular  effort 
and  not  to  any  direct  action  on  the  heart  for  Jacquet  has  shown  that  the 
pulse  rate  is  unaltered  by  alcohol  in  normal  cases,  provided  that  no 
excitement  be  produced  by  the  environment.  In  animals  also,  the 
pulse  rate  is  very  little  altered  by  alcohol,  except  in  very  large  quantities, 
when  it  is  slowed.    The  blood-pressure  is  said  to  l)e  slightly  increased 


Fig.  3 


Tracing  of  the  movements  of  tlio  ventricle  (lower)  and  auricle  (upper)  of  the  dog  wlion 
a  large  dose  (20  c.c.  or  §  oz.)  of  50  per  cent,  alcohol  is  suddenly  thrown  into  a  vein.  The 
levers  move  upward  during  systole,  downward  during  diastole.  A,  normal.  B,  in- 
jection. The  systole  of  the  auricle  is  very  much  weakened,  the  diastole  is  less  affected. 
The  ventric'ular  systole  is  comparatively  little  changed,  althougli  it  also  is  a  little  weaker. 
The  effect  jiasses  off  very  rapidly,  so  that  at  the  end  of  the  tracing  lioth  chaml)ers  have 
almost  recovered.  A  very  similar  effect  is  seen  under  chloroform.  (Fig.  10.)  (The 
tracing  is  to  be  followed  from  right  to  left.) 


in  man  in  some  cases  after  moderate  quantities  of  alcohol  (15-o()  c.c), 
but  in  at  least  an  equal  luuubcr  of  observations  it  was  foimd  to  be 
slightly  reduced,  and  in  many  no  definite  change  could  be  made  out. 
In  animals  the  blood-pressure  has  been  found  to  be  slightly  iiuTcased 
by  some  obserx'ers,  to  be  reduced  by  others.  IJrooks,  who  has  succeeded 
in  registering  the  blood-pressure  i)ainlessly  in  unana'sthetizcd  animals, 
found  that  alcohol  gi\(Mi  by  the  mouth  increased  the  arterial  tension 
for  about  five  minutes  and  then  reduced  it.     When  it  was  injected  intra- 


ALCOHOL  179 

venoiisly  or  by  a  gastric  fistula,  the  tension  was  reduced.  Alcohol  is 
believed  by  some  to  augment  the  strength  of  the  heart,  but  the  change 
is  small  in  extent  and  inconstant  in  its  appearance.  Larger  quantities 
affect  the  heart  in  the  same  way  as  ether  and  chloroform,  weakening 
the  auricular  and  later  the  ventricular  systole,  and  inducing  dilatation 
and  slowing  of  both  chambers  (Fig.  3).  The  action  of  alcohol  on 
the  heart  is  much  less  than  that  of  chloroform,  however,  about  200 
times  as  much  being  required  to  arrest  the  frog's  heart;  and  Loeb 
found  that  the  mammalian  heart  continues  to  beat  when  perfused  with 
two  per  cent,  alcohol. 

The  flushing  of  the  skin  which  occurs  in  alcoholic  intoxication  indi- 
cates dilation  of  the  skin  vessels,  and  this  is  sometimes  accomj)anied 
by  a  very  slight  constriction  of  the  vessels  of  the  internal  organs. 
These  seem  to  arise  from  central  vasomotor  action,  but  whether  it  is 
due  to  direct  stimulation  of  the  centres  or  arises  from  a  reflex  from 
the  periphery,  is  not  yet  determined.  Very  large  quantities  of  alcohol 
cause  a  marked  fall  in  the  arterial  tension,  through  weakening  the 
vaso-constrictor  centres  and  the  heart  muscle,  but  the  quantities  of 
alcohol  required  to  cause  any  great  fall  in  blood-pressure  are  far  in 
excess  of  those  used  in  therapeutics. 

On  the  whole,  the  action  on  the  circulation  of  small  quantities  of 
alcohol  (|-1  oz.)  may  be  favorable  in  some  conditions,  but  is  so  slight 
and  inconstant  that  it  is  impossible  to  regard  it  as  a  basis  on  which 
serious  therapeutics  can  be  founded.  The  slowing  of  the  heart  which 
often  follows  the  administration  of  alcohol  in  fever,  would  seem  due 
rather  to  its  diminishing  the  cerebral  excitement  than  to  its  direct 
action  on  the  heart. 

Alcohol  has  little  effect  on  Muscle  or  on  peripheral  Nerves  when  it  is  car- 
ried to  them  by  the  blood,  but  Lee  states  that  frog's  muscle  is  strengthened 
by  small  quantities  and  weakened  by  larger  amounts.  This  has  been  inter- 
preted as  indicating  that  small  quantities  of  alcohol  are  utilized  b}-  the  muscle 
as  a  source  of  energy,  while  this  effect  disappears  under  larger  ciuantities  which 
unfold  the  toxic  action  of  the  drug.  And  Durig's  experiments  show  that  in  man 
alcohol  may  be  utilized  for  work  in  the  same  way  as  the  ordinary  sources  of 
energy,  such  as  sugar.  When  the  frog's  nerve  is  exposed  to  alcoholic  vapor  its 
irritability  is  first  increased  and  later  diminished  if  the  quantity  applied  be 
large  enough.    The  sensory  fibres  are  said  to  be  depressed  before  the  motor. 

The  effect  of  alcohol  on  the  Digestion  has  been  the  subject  of  many 
investigations,  both  from  the  clinical  and  the  experimental  i)oint  of 
view.  There  exists  a  widespread  belief  in  both  lay  and  medical  circles 
that  small  quantities  of  alcohol  taken  before  a  meal  increase  the  appe- 
tite, while  after  food  they  accelerate  the  digestion.  It  is  obvious  that 
alcohol  may  affect  digestion  either  by  altering  the  activity  of  the  fer- 
ments in  the  digestive  canal,  or  by  altering  the  secretion,  movement, 
or  absorption  of  the  stomach  and  intestine.  The  digestixe  power  of 
the  ferments  outside  the  body  has  been  found  to  be  unaltered  or  slightly 
increased  when  pure  alcohol  is  present  in  very  small  quantity.  But 
when  more  than  traces  of  alcohol  are  present,  the  gastric  and  pancreatic 


180  SUBSTANCES  ACTING  AFTER  ABSORPTION 

juices  are  retarded,  and  even  small  quantities  of  the  ordinary  wines 
and  beers  have  this  detrimental  effect.  It  does  not  seem  likely  that 
the  initial  very  slight  augmentation  of  the  ferment  action  plays  any 
important  role  in  the  effects  of  alcohol  on  the  stomach. 

The  presence  of  alcohol  in  the  mouth  causes  (according  to  Chitten- 
den, INIendel  and  Jackson)  a  very  appreciable  increase  in  the  secretion 
of  the  saliva,  presumably  by  reflex  action,  and  a  similar  increase  in  the 
gastric  juice  may  probably  follow  from  its  local  irritant  action  on  the 
stomach.  But,  apart  from  this,  it  appears  to  exert  a  specific  action  on 
the  secretion  after  its  absorption  into  the  circulation.  For  when  it  is 
injected  into  the  rectum,  a  profuse  secretion  from  the  gastric  mucous 
membrane  follows,  and  when  part  of  the  stomach  is  isolated  from  the 
rest  of  the  organ,  so  that  alcohol  given  by  the  mouth  fails  to  enter  it, 
this  part  still  shares  in  the  secretion;  the  pepsin  secretion  is  not  always 
correspondingly  augmented.  It  has  been  further  demonstrated  that 
the  absorption  of  fluids  from  the  stomach  and  bowel  is  much  acceler- 
ated by  the  addition  of  alcohol,  and  the  movements  of  the  stomach  are 
said  to  be  augmented  by  moderate  quantities. 

Digestion  in  the  stomach  may  thus  be  influenced  in  two  opposite 
directions  when  alcohol  is  administered  in  the  usual  form  of  wine, 
spirits,  or  beer.  The  action  on  the  ferments  is  deleterious,  while  the 
changes  in  the  stomach  wall,  the  increased  secretion  and  movement 
and  the  accelerated  absorption,  are  beneficial  in  many  cases.  These 
two  opposing  factors  may  neutralize  each  other,  as  in  the  dog,  in  which 
the  rate  of  digestion  is  scarcely  altered,  the  retarding  effects  of  alcohol 
on  the  proteolysis  being  compensated  for  by  the  more  abundant  secre- 
tion of  the  juice,  which  continues  after  the  alcohol  is  absorbed,  and 
therefore  after  its  deleterious  effects  on  the  fermentation  have  disap- 
peared. (Chittenden,  Mendel  and  Jackson.)  In  man  the  result 
varies,  the  one  factor  predominating  in  some  cases,  the  other  in  others. 
Thus,  while  Kretschy  and  Buchner  found  that  the  digestion  of  proteins 
in  the  human  stomach  was  distinctly  retarded  by  alcohol  and  beer, 
P^ichenberg,  Wolff'hardt  and  others  state  that  small  ({uantities  of  alcohol 
or  wine  accelerate  the  digestion,  and  Gluzinsky  came  to  the  conclusion 
that  as  long  as  alcohol  remains  in  the  stomach  the  digestion  is  retarded, 
but  that  after  its  absorption  the  digestion  progresses  more  rapidly 
than  if  no  alcohol  had  been  given.  Zuntz  and  Magnus-Levy  have 
shown  that  the  addition  of  beer  to  the  dietary  does  not  afl'ect  the  ab- 
sorption and  utilization  of  the  food  by  the  tissues.  It  is  not  unlikely 
that  the  taste  has  some  influence  on  the  result,  that  in  those  who  enjoy 
the  taste  of  alcohol,  it  induces  a  more  rapid  secretion  and  an  improved 
digestion,  while  in  those  to  whom  it  is  disagreeable,  the  secretion  is 
less  altered. 

The  divergence  of  opinion  exists  only  in  regard  to  the  effects  of 
small  cjuantities,  for  all  are  agreed  as  to  the  deleterious  action  of  any 
but  moderate  doses  of  alcohol  on  the  digestion.  After  large  quantities 
(50  c.c.)  the  irritation  of  the  stomach  wall  leads  to  a  profuse  secretion 
of  nmcus,  and  to  nausea  and  \omiting.    There  is  every  reason  to  sup- 


ALCOHOL  ISl 

pose  that  this  is  due  to  the  local  irritation,  and  not  to  the  action  of  the 
absorbed  alcohol  on  the  nervous  centres.  A  large  dose  of  concentrated 
alcohol  sometimes  leaves  evidence  of  its  irritant  action  in  redness  and 
injection  of  the  mucous  membrane,  and,  it  is  said,  in  ecchymoses, 
but  in  most  cases  of  fatal  poisoning  no  such  appearances  are  to  be 
observed  after  death. 

Is  Alcohol  a  Food? — It  has  been  shown  that  only  5  per  cent,  or  less  of 
the  ingested  alcohol  is  excreted,  while  the  rest  of  that  absorbed  from 
the  stomach  and  bowel,  amounting  to  over  95  per  cent.,  undergoes 
combustion  in  the  tissues.  This  oxidation  apparently  progresses 
slowly,  appreciable  amounts  being  found  in  the  blood  twenty-four 
hours  after  its  ingestion;  this  accords  with  Kraepelin's  statement  that 
its  effect  on  the  brain  can  be  detected  for  12-24  hours.  In  undergoing 
combustion  alcohol  gives  up  energy  to  the  body,  and  therefore  is  technic- 
ally a  food,  but  this  does  not  imply  that  it  is  an  advisable  food  in  all 
conditions.  Experiments  in  which  the  carbonic  acid  excretion  was 
measured  under  alcohol  show  that  no  more  energy  is  required  for  its 
absorption  than  for  that  of  other  foods,  and  that  alcohol  taken  in  addition 
to  the  ordinary  food  is  either  itself  transformed  into  tissue,  or  under- 
goes oxidation  instead  of  some  substance  which  in  turn  is  used  to  build 
up  the  body.  Recent  investigations  seem  to  indicate  that  alcohol  is 
more  readily  utilized  by  the  tissues  than  the  carbohydrates,  even  when 
these  are  present  in  the  food  in  large  amounts;  so  that  the  administra- 
tion of  alcohol  leads  to  an  economy  in  these.  This  diminished  oxidation 
of  carbohydrates  in  the  tissues  in  turn  leads  to  the  deposit  of  fat,  which 
has  been  shown  to  occur  in  animals  treated  with  alcohol  and  is  a  common 
observation  in  man  (Togel,  Brezina  and  Diirig).  Alcohol,  therefore, 
acts  as  a  substitute  for  carbohydrates  in  the  food. 

It  has  long  been  recognized  that  when  insufficient  fat  and  carbohy- 
drate is  supplied  to  the  body,  the  proteins  are  drawn  upon  to  make 
good  the  deficiency  and  the  nitrogen  eliminated  rises  accordingly. 
On  the  other  hand,  when  the  fats  and  carbohydrates  of  the  food  are 
increased,  the  organism  economizes  its  protein  and  the  nitrogen  tends 
to  fall.  This  is  the  most  accurate  method  of  testing  the  food  value  of 
non-nitrogenous  substances,  and  alcohol  has  been  the  subject  of  a 
number  of  such  investigations,  which  have  finally  decided  this  much 
disputed  question  (Neumann,  Atwater  and  Benedict,  and  Bosemann 
and  his  pupils).  The  results  may  be  best  illustrated  by  an  account  of 
Neumann's  first  experiment. 

This  lasted  35  days,  divided  into  six  periods.  The  proteins  of  the 
food  and  the  carbohydrates  remained  constant  throughout,  while  alcohol 
was  substituted  forepart  of  the  fat  for  some  time  (see  Fig.  4).  During 
the  first  five  days  the  nitrogen  excreted  was  practically  equal  to  that 
of  the  food  (nitrogenous  equilibrium),  while  during  the  next  four 
days  one  half  of  the  fat  of  the  food  was  omitted  and  the  immediate 
result  was  an  increase  in  the  nitrogen  excreted,  indicating  that  the 
proteins  of  the  bodv  were  being  drawn  upon  to  make  good  the  deficit 
in  the  fat  of  the  food.    The  next  ten  days  a  quantity  of  alcohol  chem- 


182 


SUBSTANCES  ACTING  AFTER  ABSORPTION 


ically  c(iuivalent  to  the  fat  deficit  was  taken  and  tlie  nitrogen  elimina- 
tion slowly  fell  to  tiie  normal  (ecinilihrinm).  In  the  first  ti\e  days  of 
this  period,  iiowever,  the  nitro<]jen  remained  hifjh,  sho\vin<^  that  alcohol 
did  not  at  first  replace  the  fats  completely.  In  the  fourth  })eriod  of 
six  days,  the  same  amount  of  fat  was  given  as  at  first,  wliile  the  alcohol 
was  continued,  and  the  nitrogen  fell  much  below  the  amount  ingested; 
i.  e.,  the  alcohol  again  led  to  a  saving  of  the  proteins.  Next,  both 
alcohol  and  fat  were  omitted  for  four  days  and  the  proteid  tissues  were 
again  drawn  upon.  Finally  the  original  diet  was  resumed  and  the 
nitrogenous  equilibrium  was  at  once  restored.  From  this  experiment 
Neumann  drew  the  conclusion  that  alcohol  can  replace  a  chemically 
equivalent  amount  of  fat  in  the  dietary,  for  otherwise  the  nitrogen 
would  not  have  returned  to  the  normal  toward  the  end  of  the  third 
period;  and  alcohol  given  along  with  a  sufficient  dietary  leads  to  a 


Fiu.  4 


PAYS 
PERIODS 

FAT  OF 
FOOD 

ALCOHOL 
NITROGEN 

1 

2 

3 

71 

5 

6 

? 

« 

9 

I? 

11 

1? 

1? 

U15 

16 

iTJisjiy 

20'2l|i2J23 

2lb 

20 

27;2S 

2» 

30i3ll32'33 

a  35] 

I 

I 

I 

III 

ly 

V 

.       'yi 

'    !    i 

,In 

-^ 

•jit    !<;|^ 

i'56|g.;DAILY 

:t;  G.  DAIL>      ]     ;     J 

i73'G.; 
ioAJLY 

-V 

'N 

/ 

1     ,     ,     1     .     , 

/ 

-- 

~                         -                          \ 

/ 

N 

^ 

■N 

N 

V 

>s 

,>^ 

/•N 

\ 

/ 

\ 

•\ 

V 

V 

/ 

The  effect  of  alcohol  ou  nitrogen  elimination.  The  wave-line  represents  the  nitrogen 
excreted.  It  rises  rapidly  in  the  second  period  when  the  fat  of  the  food  was  reduced  to 
one  half,  but  soon  falls  in  the  third  period  where  alcohol  was  substituted.  100  g.  of  alco- 
hol is  chemically  equivalent  to  78  g.  of  fat.     (After  Neumann.) 


further  economy  of  the  proteins  just  as  additional  fat  would  do;  other- 
wise the  nitrogen  would  not  have  fallen  below  the  point  of  equilibrium 
in  the  fourth  period. 

The  final  result  of  all  these  investigations  is  that  alcohol  can  take 
the  i)lace  of  some  of  the  fat  in  the  food,  and  leads  to  the  same  economy 
of  protein  as  the  ordinary  non-nitrogenous  constitutents  of  the  dietary. 
The  first  three  or  four  days  during  which  alcohol  is  substituted  for  fat 
it  has  little  or  no  tendency  to  economize  the  proteins,  but  this  is  true 
of  other  forms  of  food  also,  any  sudden  change  in  the  non-nitrogenous 
food  leading  to  a  temporary  increase  in  the  nitrogen  excreted,  which 
persists  until  the  tissues  have  become  accustomed  to  the  new  dietary. 

Metabolism. — It  was  formerly  supposed  that  alcohol  economized  the 
body  tissues  in  some  ill-defined  way,  by  means  of  a  direct  action  on 
the  protoplasm  of  the  cells;  as  it  was  expressed,  alcohol  lesseneil  the 


ALCOHOL  183 

combustion  of  the  tissues.  But  moderate  quantities  of  alcohol  ajjpear 
to  have  no  action  on  the  general  metabolism  except  that  which  it  shares 
with  other  nitrogen  free  foods.  When  very  large  quantities  of  alcohol 
are  taken,  and  depression  and  sleep  follow,  the  combustion  of  the  body 
is  reduced,  not  through  any  action  on  the  protoplasm  generally,  but 
through  the  muscular  movements  being  lessened.  In  the  same  way, 
during  the  excitement  stage,  the  carbonic  acid  exhaled  is  doubtless 
much  increased,  because  more  energy  and  more  of  the  body  tissues  are 
used  up  in  the  violent  movements.  But  Mendel  and  Ililditch  state 
that  the  uric  acid  of  the  urine  is  considerably  increased  by  moderate 
quantities  in  man,  and  this  increase  is  shared  in  by  both  the  endogenous 
uric  acid  and  that  of  the  food.  This  specific  action  on  the  uric  acid 
excretion  has  not  been  explained.  The  purin  bases  are  increased  to  a 
smaller  extent,  while  the  creatinin  excretion  remains  unchanged. 

Influence  on  Infection. — Persons  addicted  to  the  use  of  alcohol  are 
known  to  show  less  resistance  in  acute  disease  and  in  operations  accom- 
panied by  shock  than  more  temperate  individuals,  and  in  very  intem- 
perate cases  the  prognosis  must  be  guarded  in  an  attack  which  would 
ordinarily  be  accompanied  with  little  danger.  This  has  been  confirmed 
by  a  number  of  experiments  on  animals  which  were  subjected  to  large 
doses  of  alcohol  and  then  inoculated  with  pathogenic  germs  (Laitinen). 
The  results  have  invariably  shown  a  greater  susceptibility  to  infection 
and  a  greater  mortality  than  in  control  animals  which  had  received 
no  alcohol.  A  similar  effect  was  observed  when  toxins  were  injected 
instead  of  bacteria,  and  great  difficulty  was  encountered  in  rendering 
animals  immune  to  the  diphtheria  toxin  if  they  had  previously  been 
treated  with  alcohol.  Various  explanations  of  this  reduced  resistance 
have  been  given,  Rubin  ascribing  it  to  paucity  or  inactivity  of  the 
leucocytes,  while  Abbot  and  Bergey  found  a  reduction  in  the  hemolytic 
complement,  which  suggests  that  the  susceptibility  to  infection  may  be 
due  to  the  failure  to  form  the  specific  complement  to  the  bacterial  toxin. 
It  is  often  stated  that  alcohol  given  in  the  treatment  of  infectious  diseases 
must  have  a  similar  deleterious  effect  on  the  resistance  of  the  tissues, 
but  this  has  not  been  shown  to  be  the  case. 

These  clinical  and  experimental  results  have  raised  the  question 
whether  the  ordinary  dietetic  use  of  alcohol  in  even  small  quantities 
(15-30  c.c.)  may  not  lead  to  impairment  of  the  resistance  to  infectious 
disease,  and  much  interest  attaches  to  Laitinen's  later  work,  in  which 
animals  were  treated  with  quantities  of  alcohol  corresponding  to  those 
habitually  used  by  temperate  persons.  The  general  result  appears 
to  be  that  the  prolonged  use  of  small  quantities  in  animals  (0.1  c.c. 
per  kilo.)  may  affect  their  susceptibility  to  disease,  but  the  average 
mortality  is  not  greater  than  that  of  the  controls  to  which  no  alcohol 
has  been  given. 

A  much  more  distinct  effect  from  small  doses  of  alcohol,  such  as 
correspond  to  temperate  use  in  man,  has  been  observed  b\-  Hunt,  who 
finds  that  animals  thus  treated  become  more  susceptible  to  the  action 
of  methyl  cyanide.       This  poison  acts  in  the  tissues  through  being 


184  SUBSTANCES  ACTING  AFTER  ABSORPTION 

oxidized  to  liydrocyanic  acid,  and  Hunt  believes  that  the  effect  of  the 
prol()nfi;cd  treatment  with  alcohol  is  to  faciHtate  tliis  oxidation,  and 
that  the  reaction  is  evidence  of  an  alteration  of  the  nietaholisni  of  the 
body  in  this  direction.  The  great  importance  of  this  observation  lies 
in  the  fact  that  the  modification  of  the  metabolism  which  it  demon- 
strates, arises  from  the  prolonged  use  of  quantities  of  alcohol  which 
are  too  small  to  give  rise  to  definite  symptoms  of  intoxication.  Appar- 
ently the  alteration  is  associated  with  the  development  of  tolerance  for 
alcohol. 

The  Temperature  of  the  body  falls  somewhat  after  the  administration 
of  alcohol,  but  this  is  not  due  to  any  diminution  in  the  oxidation  and  in 
the  heat  formed,  but  to  the  greater  output  of  heat  from  the  dilation 
of  the  skin  vessels.  The  fall  in  temperature  is  comparatively  slight, 
seldom  being  more  than  |-1°  C,  but  it  would  seem  that  exposure  to 
cold  causes  a  greater  fall  in  the  temperature  after  alcohol  than  in  normal 
conditions;  this  is  perhaps  due  to  the  temperature-regulating  mechanism 
being  rendered  less  sensitive  by  alcohol. 

The  fall  in  temperature  produced  by  alcohol  is  generally  accom- 
panied by  a  feeling  of  heat,  and  a  thermometer  applied  to  the  skin 
may  actually  show  a  rise  of  several  degrees,  because  more  warm  blood 
flows  through  the  dilated  vessels.  If  much  excitement  and  movement 
follow  the  ingestion  of  alcohol,  no  fall  in  the  temperature  may  result, 
the  increased  heat  formed  during  the  movement  compensating  for  the 
increased  output,  and  in  some  cases  a  rise  of  temperature  occurs  from 
the  same  cause.  Very  large  quantities  of  alcohol  may  lead  to  a  fall 
in  temperature  of  3-5°  C,  owing  to  the  lessened  movements  during 
unconsciousness. 

Absorption  and  Excretion.^ — Alcohol  is  absorbed  rapidly,  about  20 
per  cent,  of  that  ingested  being  taken  up  in  the  stomach  and  80  per 
cent,  in  the  small  intestine.  It  is  found  in  largest  proportions  in  the 
blood  and  the  central  nervous  system;  Grehant  found  as  much  as  6 
l)arts  per  thousand  in  the  blood  of  animals,  but  more  than  this  was 
inevitably  fatal;  in  a  case  of  deep  alcoholic  coma  in  man  the  blood 
contained  2.25  parts  per  thousand  (Sweisheimer).  Traces  remain  in 
the  blood  for  about  twenty-four  hours,  but  over  95  per  cent,  of  that 
ingested  is  oxidized  in  that  time.  The  alcohol  which  escapes  com- 
bustion in  the  tissues  is  excreted  by  the  kidneys  unchanged,'  and 
by  the  lungs.-  The  excretion  of  alcohol  by  the  lungs  is  increased  by 
nnis<-ular  exertion  and  the  consequent  hyj)eri)n<x'a,  and  that  by  the 
kidneys  may  similarly  be  increased  by  large  amounts  of  fluid;  and  more 
is  excreted  when  the  alcohol  is  taken  on  an  empty  stomach  than  when 
it  is  taken  with  food;  but  even  in  these  conditions  over  90  per  cent, 
undergoes  complete  combustion  in  the  tissues.     Traces  are  sometimes 

'  Some  of  the  alcoliol  iti  the  urine  is  conihiiied  wifli  glycuroiiic  acid  in  the  rabbit, 
hut   not  in  niun. 

-  Truces  of  alcohol  are  exhaled  by  tlie  Ijicalli.  i)ut  ctliyl  aN'ohol  fails  to  escape  in 
this  way  in  nicasunililf  quantities.  TIk;  odor  of  the  brc^ath  after  spirit  drinking  arises 
from  the  hiuhi  1  aiinhnls  and  other  by-products  present  in  these  and  not  from  the  ethyl 
uh.'oliul. 


ALCOHOL 


185 


found  in  the  sweat  and  milk,  but  there  is  no  foundation  for  tlie  lefj;end 
that  children  may  be  intoxicated,  or  acquire  a  taste  for  strong  drink 
from  the  alcohol  absorbed  in  the  milk  of  a  drunken  mother  or  wet-nurse. 
The  amount  and  quality  of  the  milk  are  imalfected  by  the  administration 
of  alcohol  (Rosemann).  Brauer  states  that  alcohol  is  eliminated  in 
some  quantity  in  the  bile  and  is  then  reabsorbed  in  the  intestine;  this 
is  more  marked  in  the  case  of  amyl  alcohol  than  in  that  of  ethyl  alcohol, 
and  the  alcohol  in  the  bile  is  accompanied  by  albumin,  epithelial  cells, 
and  casts  of  the  finer  bile  ducts. 

Repeated  doses  of  alcohol  produce  Tolerance,  which,  although  not  so 
great  as  that  acquired  for  morphine  and  nicotine,  involves  the  pre- 
scription of  double  or  triple  doses  in  persons  addicted  to  drinking. 
This  tolerance  has  been  shown  by  Pringsheim  to  arise  in  part  from 
the  tissues  acquiring  an  increased  capacity  to  oxidize  alcohol;  and  as 
oxidation  begins  almost  as  soon  as  absorption,  a  large  quantity  of 


Fig.  5 


The  percentage  of  alcohol  in  the  blood  after  givang  5  c.c.  per  kg.  to  rabbits.  The  per- 
centage is  indicated  on  the  perpendicular  line,  the  hours  after  administration  along  the 
horizontal.  The  broken  Una  represents  the  changes  in  percentage  in  a  normal  animal, 
the  unbroken  that  in  an  animal  which  had  acquired  tolerance  through  prolonged  treat- 
ment with  alcohol  previously.     '(Pringsheim.) 

alcohol  taken  by  an- habitual  drinker  may  not  lead  to  the  accumulation 
in  the  blood  of  a  sufficient  quantity  to  induce  symptoms  of  intoxication 
(Fig.  5).  But  in  addition  to  this  factor,  the  brain  reacts  less  than 
normally,  for  Sweisheimer  finds  that  a  given  concentration  of  alcohol 
in  the  Wood  induces  greater  intoxication  in  an  abstinent  than  in  a 
tolerant  person.  In  tolerance  the  amount  of  alcohol  excreted  in  the 
breath  and  urine  may  sink  to  less  than  1  per  cent.,  all  the  rest  under- 
going combustion  in  the  tissues.  The  close  relationship  between  the 
narcotics  of  the  fatty  series  is  indicated  by  the  fact  that  much  more 
chloroform  or  ether  than  usual  is  required  to  anaesthetize  persons  in 
whom  a  tolerance  for  alcohol  has  been  established. 

Although  alcohol  seems  to  increase  the  Urine  to  some  extent,  it  can- 
not be  said  to  be  a  powerful  diuretic  in  itself,  and  the  diuresis  may  be 
explained  in  large  part  by  the  quantities  of  fluid  taken  with  the  alcohol 
and  by  the  accelerated  absorption  from  the  alimentary  tract.    Some  of 


180  SURSTAXCES   ACT  IXC   AFTER  ABSORPTION 

the  spirituous  licjuors,  such  as  ^'lu,  prochicc  u  profuse  secretion  of  the 
urine,  hut  this  is  due  to  their  otlier  constituents,  and  n(xt  to  the  alcolioh 

AU'ohol  is  generally  crechted  with  Aphrodisiac  powers,  that  is,  with 
increasinu;  sexual  (k'sire,  although  no  less  an  authority  than  Shakespeare 
states  that  it  prevents  the  consurnniation  of  sexual  intercourse.  The 
unquestionable  tendency  toward  sexual  excess  observed  in  intoxication 
is  due,  not  to  any  effects  on  the  generative  organs,  but  to  the  loss  of 
self-control,  from  the  cerebral  action  of  the  poison. 

Alcohol  possesses  only  a  weak  Antiseptic  action,  for  while  the 
grow^th  of  some  bacteria  is  delayed  somewhat  in  a  1  :  1000  solution, 
many  groW'  abundantly  in  4  per  cent,  alcohol,  and  some  in  even 
stronger  solutions.  Its  disinfectant  action  has  been  the  subject  of  a 
number  of  researches  recently  and  has  been  found  to  vary  with  the 
conditions.  Dry  bacteria  may  be  exposed  to  absolute  alcohol  for 
twenty-four  hours  w'ithout  losing  their  vitality,  while  60-70  per  cent, 
alcohol  is  fatal  to  them,  and  also  to  moist  organisms.  The  explanation 
of  this  curious  observation  seems  to  be  that  alcohol  fails  to  penetrate 
microbes  unless  in  the  presence  of  water.  In  less  than  40  per  cent, 
the  action  is  very  slow%  so  that  the  limits  of  alcohol  as  a  disinfectant 
may  be  placed  at  50-70  per  cent.;  in  this  strength  it  is  equivalent 
to  about  3  per  cent,  carbolic  acid,  provided  that  it  does  not  cause 
large  precipitates  of  protein.  Many  bodies  which  are  antiseptic  when 
dissolved  in  water  have  comparatively  little  effect  when  dissolved 
in  alcohol. 

Other  simple  life  forms  are  more  susceptible  to  the  action  of  alcohol 
than  the  bacteria,  though  it  does  not  act  on  these  in  such  dilution  as 
on  the  mammalian  nerve  cell.  Even  the  plants  can  be  subjected  to  its 
influence,  showing  that  in  sufficient  quantity  it  is  a  general  protoplasm 
poison.  In  most  cases  a  stage  of  increased  activity  precedes  that  of 
depression  and  this  has  been  used  as  an  argument  in  favor  of  the  primary 
stimulant  action  of  alcohol  in  the  brain. 

Methyl  alcohol,  or  wood  alcoliol,  has  assumed  great  importance  lately  from 
a  lai<i'<'  miuihcr  of  cases  of  poisoning  having  occurred  from  its  being  substi- 
tuted for  etliyl  alcohol  as  an  intoxicant,  or  in  some  patent  remedies.  In  animal 
exj)eriments  it  is  found  that  given  in  single  doses  it  is  slightly  less  poisonous 
than  ethyl  alcohol,  the  action  coming  on  somewhat  more  slowly,  but  lasting 
a  longer  time;  the  symptoms  of  gastric  irritation  are  generally  more  marked 
than  those  induced  by  ethyl  alcohol,  and  very  often  some  convulsive  move- 
ments are  observed  (Hunt).  When  the  atlministration  is  repeated,  methyl, 
alcohol  is  found  much  more  poisonous  than  ethyl,  and  this  may  jM-obably 
he  ascribed  to  the  more  jjrolonged  action  of  the  former.  Thus  it  has  been 
shown  that  when  equal  amounts  of  methyl  and  ethyl  alcohol  are  administered 
to  animals,  over  a  third  of  the  methyl  alcohol  can  lie  found  in  the  tissues  after 
forty-eighl  hours,  while  of  the  eth.vl  alcohol  only  al)out  one-tenth  remains  aft(>r 
lii'tccn  hours.  About  40  \)vr  cent,  of  the  methyl  alcohol  is  oxidi/ed  in  forty-eight 
hours,  while  2.")  per  cent,  escaiu's  in  the  breath  and  urine.  Pohl  has  pointed  out 
I  hat  while  etliyl  alcohol  undergoes  complete  combustion  in  the  tissues,  methyl 
alcohol  is  oxidizcMl  to  h)rmic  acid  and  jxissihly  to  formic  aldehyde,  both  of  which 
are  nnich  more  ))oisonous  than  the  original  alcohol.  It  seems  a  fair  inference 
that  th(>  i)rolonged  action  and  the  cons{>(|ueiit  greater  toxicity  of  tiu^  lower 
alcohol  may  he  due  to  these  products. 


ALCOHOL  187 

In  man  tlie  symptoms  of  wood  alcohol  poisoninfj;  differ  from  those  of  onli- 
nary  spirits  in  the  marked  museular  weakn(\ss  and  defective  cardiac  action, 
which  are  followed  by  nausea,  vomiting,  coma,  or  delirium  of  a  nuich  more 
intense  and  j^ersistent  character  than  those  seen  in  intoxication  with  ethyl 
alcohol.  In  a  considerai)le  number  of  cases  death  has  followed  from  a  single 
dose  smaller  than  would  have  been  fatal  had  ethyl  alcohol  been  swallowed, 
and  in  some  cases  total  and  permanent  blindness  lias  followed  or  accompanied 
recovery.  This  condition  is  more  often  the  result  of  repeated  ingestion  of  the 
alcohol,  however,  and  is  due  to  optic  neuritis  and  subsequent  complete  optic 
atrophy.  The  large  number  of  cases  of  blindness  or  fatal  intoxication  collected 
by  BuUer  and  Wood  demonstrate  clearty  the  danger  incurred  in  the  use  of 
this  poison  internallj'  or  even  externallj' ,  or  by  inhalation  of  its  vapor.  Optic 
atrophy  has  been  induced  in  animals  repeatedly  by  the  administration  of  wood 
alcohol  while  it  is  hardl}^  liable  to  occur  from  ethyl  alcohol. 

The  other  alcohols  are  mainly  of  interest  as  impurities  of  the  preparations 
of  ethjd  alcohol.  They  all  resemble  it  in  their  general  efTects,  but  differ  from 
it  in  toxicity;  propyl  alcohol  is  more  powerful  than  ethyl,  butyl  than  propyl, 
and  amj'l  than  any  of  them.  Amyl  alcohol,  or  fusel  oil,  is  present  in  small 
c[uantity  in  most  forms  of  spirits.  It  resembles  ethylic  alcohol  in  general,  but 
is  more  irritant  localh^,  and  is  believed  by  some  authorities  to  have  more  deleter- 
ious effects  in  chronic  poisoning  than  pure  ethjdic  alcohol.  This  is  not  based 
on  any  very  satisfactorj'  evidence,  however,  and  all  the  characteristic  symp- 
toms of  chronic  alcoholism  have  been  produced  in  animals  by  pure  ethyl  alcohol. 
Furfurol  is  also  present  in  many  forms  of  spirits,  but  in  such  small  quantities  that 
it  does  not  play  an)'  role  in  the  sj'mptoms  induced  by  them. 

Preparations. 

Alcohol  (U.  S.  P.)  contains  92  per  cent,  of  alcohol  (C2H5HO)  by  weight. 

Alcohol  Absolutum  (U.  S.  P.,  B.  P.),  absolute  alcohol,  contains  not  more 
than  1  per  cent.,  by  weight,  of  water. 

Alcohol  Dilutum  (U.  S.  P.)  contains  about  41  per  cent.,  by  w-eight,  of  alcohol. 

Spiritus  Rectificdtus  (B.  P.),  rectified  spirit,  contains  90  parts  of  pure  alcohol, 
by  volume,  and  10  parts  of  w^ater  (85.65  per  cent.,  by  weight,  of  alcohol). 
There  are  four  official  dilutiors  in  the  B.  P.,  containing  70,  60,  45,  and  20  per 
cent,  of  alcohol  by  volume  respectively. 

Spiritits  Frumenti  (U.  8.  P.),  whiskey,  contains  44-50  per  cent,  of  alcohol 
by  weight,  and  is  obtained  by  distillation  of  an  extract  of  fermented  grain. 

"Spiritus  ViNi  Gallici  (U."^S.  P.),  brandy,  contains  39-47  per  cent,  of  alcohol 
by  weight,  and  is  obtained  by  the  distillation  of  fermented  grape  juice. 

Non-pharmacopceial  spirits,  which  are  used  occasionally  in  medicine,  are 
gin  and  rum. 

These  Spirits  all  contain,  roughly  speaking,  about  30-40  per  cent,  of  alcohol 
along  with  other  volatile  substances,  some  of  which  are  alcohols  of  the  same 
series  as  ordinary  alcohol  (butjdic,  amylic,  etc.),  while  others  are  of  entirely 
unknown  constitution— the  oenanthic  ethers.  Brandy  and  whiskey  act  very 
much  in  the  same  way  as  pure  alcohol.  When  freshh'  distilled  they  are  more 
irritant  and  less  pleasantly  flavored  than  when  kept  for  some  years  but  do 
not  seem  more  deleterious.  Numerous  other  preparations  containing  large 
quantities  of  alcohol,  such  as  the  spirits  of  the  volatile  oils,  might  also  be  m- 
cluded  in  this  group,  but  they  are  not  used,  as  a  general  rule,  for  the  same 
purposes  as  the  alcoholic  preparations  proper,  and  their  elTects  are  in  part 
due  to  the  volatile  oils  contained.  Some  of  them  have,  however,  been  em- 
ployed as  intoxicants  instead  of  brandy  or  whiskey,  and  Eau  de  Cologne  and 
other  essences  have  gained  a  certain  notoriety  as  a  means  of  secret  drinking 
among  w^omen.  The  liqueurs  are  too  numerous  to  mention,  and  their  com- 
-  position  is  extremelv  diverse.  ]\Iany  of  them  contain  considerable  quanti- 
ties of  sugar,  and  the  combination  of  alcohol  and  sugar  woukl  seem  peculiarly 


ISS  SUBSTANCES  ACTING  AFTER  ABSORPTION 

deleterious  to  the  gastric  mucous  membrane.  Others,  such  as  cherry  water 
(Kirs(;h\vasser),  contain  liydrocyanic  acid,  and  the  others  various  bodies  of  the 
volatile  oil  series.  None  of  them  seem  to  have  any  properties  which  would 
reconunond  their  use  in  therapeutics. 

The  Wines  and  Beers  are  mucli  weaker  i)rcparations  of  alcohol,  the  lighter 
wines  (hock  and  claret)  containing  about  G-8  per  cent,  ethyl  alcohol,  while  in 
sherry  and  port  it  may  amount  to  15-20  per  cent.  In  addition,  the  wines 
contaiii  the  same  volatile  constituents  as  brandy,  although  in  smaller  amounts. 
The  red  wines  contain  a  form  of  tannic  acid  derived  from  the  skin  of  the  grapes, 
and  both  red  and  white  often  contain  considerable  quantities  of  acids,  chiefly 
tartaric  acid.  The  amount  of  sugar  varies  with  the  different  wines,  and  in  fact 
in  wine  from  the  same  locality  but  of  different  seasons.  These  constituents  may 
lend  to  the  wines  a  local  deleterious  action  on  the  stomach,  more  especially 
when  they  are  taken  habitually.  Champagne  and  the  other  sparkling  wines 
contain  large  quantities  of  carbonic  acid,  which  acts  as  a  stimulant  to  the 
gastric  mucous  membrane.  Champagne  is  considered  one  of  the  most 
"stimulant"  of  alcoholic  preparations,  although  it  contains  a  verj'^  low  per- 
centage of  alcohol  compared  with  spirits,  a  fact  which  is  of  some  significance 
in  the  explanation  of  the  "stimulant"  effects  of  alcohol. 

The  beers  are  not  pharmacopocial,  and  are  less  frequently  advised  than  the 
other  preparations.  They  generally  contain  a  comparatively  small  percentage 
of  alcohol  (4-10  per  cent.),  along  with  a  large  amount  of  solids.  These  solids 
consist  mainly  of  dextrin,  sugar,  and  other  starch  products,  which  retard  the 
absorption  of  the  fluid,  but  are  of  considerable  value  as  foods.  The  hops  added 
in  the  preparation  have  probably  no  action  save  as  bitter  stomachics.  The 
alcohol  of  beer  is  comparatively  slowly  absorbed  owing  to  the  colloid  constituents, 
and  this  allows  time  for  fermentation  changes  in  the  sugars  and  dextrins,  which 
may  perhaps  account  for  the  discomfort  produced  by  malt  liquors  in  persons 
of  feeble  digestion.  When  beers  and  porter  do  not  derange  the  digestion,  they 
are  the  most  nutritive  of  all  the  alcoholic  preparations,  owing  to  the  large  amount 
of  carboh}'drates  they  contain. 

Therapeutic  Uses. — Alcohol  is  used  externally  in  very  dilute  solution 
as  a  cooling  application  to  the  skin,  and  in  threatening  bedsores,  in 
which  it  is  often  applied  as  brandy,  whiskey,  or  dilute  alcohol  in  order 
to  harden  the  epidermis.  It  has  been  employed  as  an  antiseptic  and 
mild  irritant  to  broken  surfaces,  and  if  applied  to  the  skin  in  concen- 
trated form,  and  especially  if  kept  from  evaporation,  acts  as  a  rubefa- 
cient and  irritant.  Its  use  to  wash  the  skin  and  hands  before  operations 
arises  from  its  power  of  cleansing  the  skin  and  removing  the  oils  and 
fats  rather  than  from  its  exercising  any  disinfectant  action.  In  tlie 
form  of  diluted  claret  it  is  not  infrequently  used  as  an  astringent  gargle. 

The  indications  for  the  internal  use  of  alcoliol  are  ill  defined,  and 
cases  which  one  physician  would  treat  with  alcohol  often  seem  to  pro- 
gross  as  favorably  without  it  in  the  hands  of  another.  It  has  been 
prescribed  very  largely  in  the  past  as  a  "stimulant"  under  the  impression 
that  it  increases  the  activity  of  the  circulation,  respiration,  and  other 
functions  of  the  body.  The  basis  for  this  belief  has  been  discussed 
aheady,  and  the  results  may  be  stated  shortly:  alcohol  may  i)romote 
the  vital  functions  to  a  slight  extent,  but  this  action  is  very  transient 
and  inconstant  in  its  occurrence  and  is  quite  insufficient  basis  for  any 
therapeutic  application.  The  action  which  lends  alcohol  its  value  in 
tbcrapeutics  is  not  its  stinudant  but  its  narcotic  action,  which  allays 
the  aii\iet\'  and  distress  of  the  patient,  promotes  rest  and  sleep,  and  thus 


ALCOHOL  189 

aids  toward  healing,  or  at  the  worst  renders  iUness  more  tolcrahle. 
Small  quantities  of  other  narcotics  might  be  substituted  for  alcohol, 
but  none  of  them  perhaps  excel  it  in  producing  that  spirit  of  hopeful- 
ness and  restful  confidence  which  contributes  so  much  to  recovery. 

One  series  of  symptoms  which  is  often  treated  with  wines  is  of  gastric 
origin,  and  is  manifested  in  want  of  appetite  and  enfeeblement  of 
the  digestion;  in  some  of  these  cases  the  alcoholic  preparations  seem  to 
be  beneficial,  while  in  others  they  appear  to  be  positively  harmful. 
This  may  be  explained  by  the  effect  of  alcohol  on  secretion  and  absorp- 
tion, only  those  cases  in  which  secretion  is  deficient  being  benefited, 
but  the  tastes  of  the  patient  are  a  more  important  factor;  if  he  enjoys 
the  taste  and  odor  of  wine,  its  administration  may  promote  his  appetite, 
while,  on  the  other  hand,  if  he  has  a  distaste  for  wine,  it  will  i)rove 
harmful.  There  is  no  question  that  the  functions  of  the  stomach  are 
increased  by  pleasing,  and  retarded  by  unpleasant  tastes  and  odors. 
In  these  cases  "dry"  wines  are  to  be  preferred,  as  the  sugar  of  the 
sw^eet  wines  may  irritate  the  stomach;  champagne  may  be  used,  and 
the  wine  ought  to  be  given  immediately  before  or  during  a  meal. 

Cases  of  hemorrhage,  shock  and  other  forms  of  severe  and  sudden 
depression  of  the  heart  and  central  nervous  system  are  very  frequently 
"  treated  by  the  administration  of  strong  alcoholic  preparations,  such  as 
brandy  and  whiskey,  this  treatment  being  based  upon  the  belief  that 
alcohol  is  a  cardiac  and  respiratory  stimulant.  It  is  extremely  difficult 
to  estimate  the  value  of  a  remedy  in  these  conditions,  and  it  is  possible 
that  it  may  be  of  benefit  in  some  cases  by  lessening  the  anxiety  and  pain 
of  the  patient  if  he  is  conscious.  But  the  beneficial  effects  of  alcohol  in 
these  cases  has  been  much  questioned  in  recent  years,  and  the  belief 
that  it  is  of  little  value  is  certainly  more  widely  held  at  present  that  at 
any  previous  time;  in' experimental  shock  in  animals,  Crile  found  that 
alcohol  generally  increased  the  danger  when  given  in  average  doses, 
and  that  smaller  doses  had  no  beneficial  effects,  but  it  is  quite  possible 
that  in  man  different  results  may  be  obtained,  from  alcohol  acting  as  a 
narcotic  and  removing  nervous  symptoms  which  would  not  arise  in 
the  lower  animals.    In  unconsciousness  it  is  probably  of  no  value. 

In  sudden  chill  with  a  tendency  to  fever,  alcohol  is  often  of  great 
benefit,  especially  when  taken  in  the  form  of  brandy  or  whiskey 
diluted  with  hot  water.  Its  efficacy  here  would  seem  due  to  the  relief  of 
the  congestion  of  the  internal  organs  by  the  return  of  the  blood  to  the  skin. 
In  many  cases  of  acute  inflammatory  disease,  the  prescription  of 
alcohol  seems  to  be  attended  with  benefit,  while  in  others  it  seems 
rather  to  increase  the  severity  of  the  symptoms.  No  special  indications 
can  be  given  for  alcohol  in  these  cases,  and  the  physician  must  be 
guided  by  its  effects.  It  may  tend  to  allay  the  irritability  of  the  nervous 
centres,  and  thus  reduce  the  delirium  and  slow  the  heart  and  respiration 
by  lessening  the  muscular  movement;  Cabot  and  Dening  and  his 
pupils  state  that  the  administration  of  alcohol  to  patients  is  not  followed 
by  any  significant  rise  of  blood-pressure,  but  by  a  slight  fall  in  most 
cases.      Moreover,  the  tissue  waste  is  much  increased  in  fever,  and  at 


lUl)  SUli.STAXCES   ACTJXa   AFTER   ABSOlil'TWN 

the  same  time  the  food  absorption  is  less  than  normally,  so  that  many 
of  the  symptoms  may  be  dne  to  starvation  of  the  tissues.  The  food- 
value  of  aleohol  is  unehanged  l\v  the  presenee  of  fever  (Ott) ;  it  demands 
less  energy  from  the  digestive  organs  than  fats  and  starehy  foods,  and 
has  a  higher  value  as  a  producer  of  energy  than  sugar.  It  cannot 
supply  the  place  of  the  nitrogenous  foods,  but  given  along  with 
them,  may  lead  to  a  greater  economy  of  the  tissues.  Strong  wines 
or  diluted  spirits  are  generally  employed  here  and  ought  to  be  given 
in  small  quantities  frequently. 

Alcohol  was  formerly  advocated  especially  in  septic  conditions,  and 
here  it  may  be  of  value  on  the  same  grounds  as  in  acute  fevers, 
although  it  does  not  seem  to  have  any  specific  action  in  septic  dis- 
ease, as  was  once  believed.  A  protest  has  recently  been  raised  against 
the  use  of  alcohol  in  these  cases,  on  the  ground  that  animals  subjected 
to  alcohol  succiuub  more  readily  to  infection  than  controls  which 
have  received  no  treatment,  and  this  has  been  shown  to  be  true  even 
when  the  dose  of  alcohol  was  proportionate  to  that  often  advised  in 
the  treatment  of  these  cases  in  man  (Laitinen).  This  is  undoubtedly 
an  objection  of  great  weight,  but  it  must  not  be  forgotten  that  though 
alcohol  may  be  deleterious  in  this  way,  this  may  be  more  than  compen- 
sated for  by  its  value  as  a  food  and  by  its  narcotic  effects  allaying 
the  nervous  irritability^  and  promoting  sleep;  this  narcotic  action  may 
very  well  be  conceived  to  be  of  benefit  to  man,  while  actually  prejudicial 
to  animals. 

In  some  chronic  forms  of  nervous  disease  alcohol  may  also  be  of 
value,  although  its  administration  must  always  be  guarded,  owing  to 
the  tendency  to  the  formation  of  the  alcohol  habit.  Thus,  in  some 
forms  of  melancholia  and  of  neuralgia  it  gives  relief,  and  some  authorities 
recommend  its  use  in  small  quantities  in  cases  of  distress  of  mind  from 
any  cause,  such  as  grief,  business  anxiety  or  depression;  undoubtedly 
alcohol  improves  these  conditions  by  its  narcotic  action  on  the  brain, 
but  the  danger  of  the  alcohol  habit  is  so  great  that  many  physicians 
refuse  to  take  the  responsibility  of  prescribing  the  drug  in  these  cases. 

In  certain  forms  of  brain  defect,  notably  in  epilepsy,  alcohol  often 
acts  with  unusual  power  and  sometimes  appears  to  cause  a  prolonged 
nervous  disturbance  which  is  very  deleterious  in  these  subjects. 

In  chronic  conditions  of  cachexia  and  loss  of  flesh  in  general,  and 
during  convalescence,  alcoholic  i)reparations  are  often  advised  simply 
as  foods,  and  in  these  cases  the  ales,  beers  and  ])orters  are  generally  to 
be  preferred  to  the  others,  })rovided  always  that  the  stomach  is  not 
irritated  by  them,  as  they  contain  other  foodstuffs  of  value  in  addition 
to  the  alcohol. 

In  poisonous  snak(>  bite,  alcohol  is  generally  adininistcrcd  in  enor- 
mous (piantities,  either  as  whiskey  or  brandy,  but  it  is  really  of  no 
value  in  these  cases. 

Alcohol  is  of  value  as  a  mild  hypnotic,  a  comparati\ely  small  (piaiitity 
taken  before  retiring  being  often  suflicient  to  st'cure  (piiet  and  refreshing 
sleep.     Beer,  or  spirits  and  water,  is  generally  usetl  for  this  purpose. 


ALCOHOL  191 

Brandy  has  a  certain  reputation  in  the  treatment  of  the  milder 
forms  of  diarrhoea,  while  the  other  spirits  have  no  effect  in  this  condition. 
The  way  in  which  it  acts  here  is  imknown. 

In  the  prescription  of  alcohol,  the  ordinary  spirits,  brandy  or 
whiskey,  are  very  much  more  frequently  advised  than  the  pure 
preparations,  as  the  latter  are  more  apt  to  pall  upon  the  taste  of  the 
patient.  Both  of  these  spirits  ought  to  be  diluted  with  at  least  an 
equal  quantity  of  water.  The  wines  are  more  used  in  chronic  condi- 
tions, although  diluted  spirits  may  be  advised  here  also.  Beers  are 
employed  only  in  debility  unaccompanied  by  gastric  symptoms. 

Alcohol  can  be  given  to  children  in  relatively  larger  quantities  than 
to  adults,  and  again  in  old  age  no  such  reduction  in  the  dose  is  recjuired 
as  in  the  case  of  many  other  drugs.  Where  a  tolerance  for  alcohol 
has  been  established,  the  dose  has  often  to  be  more  than  doubled  in 
order  to  have  any  effect,  and  in  acute  febrile  conditions  very  large 
quantities  of  alcohol  are  often  given  without  intoxication,  though  it 
seems  questionable  whether  an  equally  beneficial  result  could  not  be 
attained  with  much  smaller  doses.  In  gastric  irritation,  most  prepa- 
rations of  alcohol  are  contra-indicated,  but  champagne  is  often  of 
benefit  in  checking  vomiting,  especially  that  of  pregnancy  and  of  sea- 
sickness, this  effect  being  due  to  the  carbonic  acid,  not  to  the  alcohol. 
In  nephritis  and  other  inflammatory  conditions  of  the  genito-urinary 
tract,  alcohol  is  generally  avoided  on  account  of  its  supposed  effects  on 
the  epithelium. 

In  regard  to  the  Habitual  Use  of  Alcohol  by  healthy  persons,  all  authori- 
ties agree  that  it  is  a  luxury,  that  it  is  entirely  unnecessary  for  the 
growth  and  maintenance  of  the  body,  and  that  it  neither  promotes 
greater  healthfulness  nor  in  any  way  retards  the  onset  of  disease.  It  is 
true  that  it  is  utilized  by  the  body  as  a  food,  but  its  value  as  such  is 
limited  because  only  small  quantities  can  be  taken  without  disturbance 
of  the  nervous  system.  At  the  same  time  it  is  difficult  to  prove  that 
the  moderate  use  of  alcohol  is  injurious,  for  when  taken  after  work 
it  seems  to  cause  no  impairment  of  the  capacity  for  work  next  day  and 
often  seems  to  remove  the  sense  of  fatigue.  And  in  many  it  undoubt- 
edly promotes  happiness  and  allays  the  worries  and  anxieties  of  life. 
Attempts  have  been  made  to  show  that  even  the  moderate  use  of 
alcohol  lessens  the  resistance  to  the  onset  of  disease,  but  these  have 
not  been  successful.  There  are,  however,  two  considerations  which  may 
be  brought  against  the  use  of  alcohol  even  in  the  most  strictly  limited 
quantities.  The  first  of  these  is  drawn  from  the  statistics  of  life  insurance, 
in  which  it  is  found  that  the  prospects  of  longevity  are  considerably 
better  for  total  abstainers  than  for  even  moderate  users  of  alcohol. 
The  second  is  that  in  a  small  percentage  of  persons  the  moderate  use 
of  alcohol  leads  to  chronic  alcoholism. 

The  habitual  indulgence  in  alcohol  to  excess  is  more  easily  intelligilile 
than  some  other  chronic  intoxications,  for,  unlike  nicotine,  alcohol 
is  taken  not  only  for  its  local  effects  on  the  organs  of  taste  and  on  the 
mucous  membranes  of  the  mouth  and  stomach,  but  also  for  its  action 


192  SUBSTANCES  ACTING  AFTER  ABSORPTION 

on  the  brain  in  numbing  the  consciousness  of  unhappiness,  and  this 
weakening  of  the  higher  sensibiUties  by  drink  is  generally  the  object 
sought  by  the  drunkard.  lie  finds  that  under  alcohol  his  habitual 
depression  disappears,  and  he  loses  the  sense  of  degradation  and  remorse 
which  possesses  him  when  sober.  The  depression  returns  in  exaggerated 
form  after  the  effects  of  the  drug  have  passed  off,  but  it  can  be  removed 
again  by  the  same  means,  and  in  this  way  the  habit  is  formed,  each 
successive  dose  being  rendered  necessary  by  the  depression  produced 
by  its  predecessor.  This  descent  into  chronic  drunkenness  is  facilitated 
by  the  lessening  of  the  self-control,  owing  to  the  action  of  alcohol  on  the 
brain.  The  victim  may  form  the  best  of  resolutions,  but  his  impaired 
will  power  and  self-control  are  unable  to  carry  them  out. 

The  symptoms  of  Chronic  Alcoholism  are  unfortunately  common,  but 
may  be  treated  better  in  detail  in  connection  with  various  forms  of 
disease,  with  which  they  are  associated  more  closely  than  with  the 
efl'ects  produced  by  the  medicinal  use  of  the  drug.  The  earliest  symp- 
toms are  generally  observed  in  the  stomach,  throat  and  larynx,  and 
consist  of  a  chronic  catarrh,  which  is  often  accompanied  by  skin  affec- 
tions, such  as  injection  of  the  cutaneous  vessels  (especially  of  those  of 
the  face),  acne,  or  pustular  eruptions.  Fatty  degeneration  occurs  in  the 
liver  especially,  and  is  said  to  be  accompanied  by  a  marked  decrease  in 
the  lecithin  and  other  lipoids  of  the  cells.  Cirrhosis  of  the  liver  is  not 
now  believed  to  be  the  direct  result  of  alcoholism.  Fatty  degeneration 
is  also  found  in  the  arterial  walls  throughout  the  body,  and  favors  the 
development  of  atheroma  and  arteriosclerosis,  which  may  lead  to 
small  aneurysmal  dilatations,  ecchymoses,  or  apoplexy.  The  heart 
undergoes  more  or  less  fatty  change,  which  is  accompanied  by  dilatation 
and  weakness.  In  the  central  nervous  system,  the  nutrition  is  imperfect 
owing  to  the  vascular  changes,  but  in  addition  to  this,  alcohol  has  a 
special  action  on  the  neurons,  which  is  betrayed  by  the  disappearance 
of  the  chromatin  granules,  and  eventually  by  shrinkage  of  the  whole 
cell.  These  alterations  in  the  central  nervous  system  lead  to  impairment 
of  memory,  self-control  and  the  other  higher  mental  processes.  Tremor, 
convulsive  attacks,  hallucinations  and  mania  are  eventually  followed 
by  idiocy  and  paralysis  in  the  worst  forms  of  the  disease.  The  periph- 
eral nerves  seem  to  be  acted  on  directly  as  well  as  through  the  changes 
in  the  centres,  for  neuritis  has  been  frequently  observed,  ending  in 
local  paralysis.  A  form  of  amblyopia  commencing  by  atrophy  of  the 
retinal  ganglion  cells  and  later  extending  to  the  fibres  of  the  optic 
nerve  has  recently  received  some  attention;  it  is  nuich  more  readily 
elicited  by  methyl  than  by  ethyl  alcohol.  A  characteristic  result  of 
chronic  alcoholism  is  dcUrimn  tremens,  an  acute  attack  of  insanity, 
which  is  liable  to  occur  after  any  shock,  such  as  haemorrhage  or  acute 
disease,  but  which  is  said  to  be  also  produced  by  the  sudden  withdrawal 
of  alcohol,  and  sometimes  occurs  without  any  apparent  innncdiate 
cause.  It  is  characterized  by  tremor,  ])erspiration,  sleeplessness,  fear, 
excitement,  and  hallucinations  of  the  various  senses,  which  differ  from 
many   other   hallucinations   of  insanity  in  consisting  of  the  nuiltiple 


ALCOHOL  193 

appearance  of  the  same  object.  These  ()l)jects  are  often  animals,  siicli 
as  snakes,  rats,  dogs,  but  the  halhicinations  are  not  confined  to  those 
of  sight,  for  whispering  voices  are  comphiined  of  not  infrequently. 

The  more  severe  forms  of  chronic  alcohohsm  are  confined  ahnost 
entirely  to  the  drinkers  of  undiluted  spirits.  Beers  and  wines  seldom 
cause  any  distinct  lesions  in  the  brain  in  themselves,  unless  spirits  are 
also  indulged  in.  The  abuse  of  the  weaker  preparations  of  alcohol  is 
always  liable  to  lead  to  that  of  the  stronger,  however,  as  tolerance  is 
established  and  the  former  lose  their  effect.  The  combination  of  spirits 
and  malt  liquors  is  said  to  be  more  hable  to  produce  deUrium  tremens 
than  the  abuse  of  either  alone. 

The  disastrous  effects  of  the  abuse  of  alcohol  are  seen  in  the  statistics 
of  the  hospitals,  prisons,  and  asylums  in  nearly  all  countries,  but  more 
especially  in  those  in  which  the  population  is  addicted  to  spirits.  A 
large  percentage  of  crimes  are  admittedly  done  under  the  influence  of 
alcohol  or  as  a  direct  result  of  alcoholic  excess,  which  is  also  responsible 
for  a  large  part  of  the  poverty  and  misery  of  the  lowest  classes  of  the 
population.  A  considerable  proportion  of  the  admissions  to  lunatic 
asylums  is  also  often  ascribed  to  alcoholism,  although  IMott  has  pointed 
out  that  this  factor  is  not  infrequently  exaggerated.  And  it  must  be 
taken  into  account  that  only  the  more  extreme  cases  come  under  the 
categories  of  criminals  or  lunatics,  and  the  enormous  number  of  cases 
of  disease  directly  caused  or  aggravated  by  the  lesions  due  to  alcohol 
escapes  recognition.  At  the  same  time,  it  is  beginning  to  be  appreciated 
that  chronic  alcoholism  itself  is  probably  due  to  a  mental  defect,  so  that 
in  a  certain  number  of  these  cases  of  insanity  and  crime,  the  over- 
indulgence in  alcohol  must  probably  be  considered  a  symptom  and 
not  a  cause.  On  the  other  hand,  alcoholic  excess  aggravates  the  mental 
defect  in  these  cases  both  by  its  direct  action  and  through  the  social 
and  economic  disabilities  which  arise  from  it;  and  this  aggravation 
of  a  congenital  weakness  can  be  avoided  only  by  abstention  from 
alcoholic  beverages.  Attempts  have  been  made  of  late  years  to  demon- 
strate that  the  effects  of  alcohol  are  hereditary,  that  the  children  of 
alcoholists  supply  a  larger  proportion  of  cases  of  insanity  and  crime 
than  those  of  the  rest  of  the  population.  It  would  seem  more  probable, 
however,  that  the  alcoholic  excesses  of  the  parent  have  no  direct  effect 
on  the  off'spring,  except  in  their  nutrition  at  birth,  but  that  the  mental 
defect  which  leads  to  alcoholic  excess  in  the  one  generation  is  inherited 
and  leads  to  crime  or  insanity  in  the  next.  The  deleterious  effect 
of  the  alcoholic  habit  in  the  parent  on  the  nutrition  of  the  offspring 
is  a  well-established  fact.  It  has  been  shown  experimentally  by 
Hodge,  who  states  that  only  a  small  percentage  of  the  puppies  born 
of  parents  treated  with  alcohol  survive,  and  further  that  tlic>-  are 
peculiarly  liable  to  infectious  disease,  such  as  distemper. 

The  treatment  of  acute  alcolwlic  intoxication  is  to  evacuate  the  stomach 

by  means  of  the  soft  elastic  tube.    The  patient  ought  to  be  put  in  bed 

and  kept  warm,  as  there  is  a  tendency  to  a  marked  fall  in  the  body 

temperature.     In  case  of  great  congestion  of  the  brain,  cold  may  be 

13 


194  SUBSTANCES  ACTING  AFTER  ABSORPTION 

applied  in  tlie  form  of  ice-bags  to  the  head,  and  some  authorities  recom- 
mend hleeding.  In  cases  of  extremely  deep  unconsciousness,  nervous 
stimulants,  such  as  caffeine  or  strychnine,  may  be  had  recourse  to,  and, 
as  a  last  resort,  artificial  respiration. 

Chronic  alcoholism  is  to  he  treated  by  the  withdrawal  of  the  poison, 
and  this  is  l)est  done  gradually,  as  the  immediate  stoppage  may  lead  to 
delirium  tremens.  It  is  often  necessary  to  incarcerate  the  patient  in 
some  retreat.  A  large  number  of  drugs  have  been  advocated  in  these 
cases,  some  of  them,  such  as  opium,  acting  as  substitutes  for  alcohol, 
others  (capsicum)  replacing  the  local  action  on  the  stomach.  The  use 
of  opium  and  other  narcotics  may,  however,  lead  to  a  craving  for  these 
which  is  quite  as  serious  as  the  original  condition.  Another  method 
of  treatment,  which  appears  to  be  successful  in  some  cases,  is  the  addi- 
tion of  nauseating  drugs  such  as  ipecacuanha  or  apomorphine  to  the 
alcohol  which  is  supplied  to  the  patient.  The  association  of  nausea 
with  liquor  eventually  becomes  so  strong  that  alcohol  in  any  form 
becomes  distasteful.    The  organic  lesions  must  be  treated  individually. 

The  treatment  of  delirium  tremens  generally  consists  in  the  use  of 
chloral  or  opium  to  lessen  the  excitement.  It  is  often  necessary,  or  at 
any  rate  advisable,  in  these  cases  to  allow  small  quantities  of  alcohol, 
as  the  sudden  withdrawal  may  aggravate  the  condition. 

Bibliography. 

An  admirable  critical  survey  is  given  by  Abel,  Atwater,  Chittenden,  and  Welch,  in 
Physiological  Aspects  of  the  Liquor  Problem,  Boston  and  New  York,  1903. 

G.  Rosenfeld.  Der  Einfluss  des  Alkohols  auf  den  Organismus.  Wiesbaden,  1901 
(very  complete  bibliography). 

Binz,  Jaksch.     Verhandl.  des  VII,  Congress  f.  innere  Medicin,  1888,  pp.  70,  86. 

Bunge.     Die  Alkoholfrage,  Leipzig,  1887. 

Jacquet.     Die  Stcllungsnahnie  des  Arztes  zur  Abstinenzfrage,  Basel,  1896. 

Pohl.    Arch.  f.  exp.  Path.  u.  Pharm.,  xxxi,  p.  281.    Schmiedeberg's  Festschrift,  p.  427. 

Chittenden  and  Mendel.    Amer.  Jour,  of  the  Med.  Sciences,  1896,  p.  35. 

Kraepelin.  Ueber  die  Beeinflussung  einfacher  psj'chischer  Vorgange  durch  einige 
Arzncimittel,  Jena,   1892.     And  in  Kraepelin's  Psychologische  Arbeiten,  i-iv,  passim. 

Rivers.    The  influence  of  alcohol  and  other  drugs  on  fatigue,  London,  1908. 

Ndcke.     Dcutsch.  Arch.  f.  klin.  Med.,  xxv,  p.  416.     (Delirium  tremens.) 

Baer.    Arch.  f.  (Anat.  u.]  Phys.,  1898,  p.  283. 

Spiro.     Miinch.  med.  Woch.,  1901,  p.  1871. 

Chittendeii,  Mendel,  and  Jackson.    Amer.  Journ.  of  Phjsiol.,  i,  p.  164. 

Brauer.     Ztschr.  f.  physiol.  Chem.,  xl,  p.  182. 

Pringsheim.    Biochem.  Ztschr.,  xii,  p.  143. 

Reid  Hunt.    Hygienic  Laboratory  Report,  No.  33,  Washington,  1907. 

Durig.     Arch.  f.  d.  ges.  Phys.,  cxiii,  pp.  213.  341. 

Schumberg.    Arch.  f.  [Anat.  u.]  Pliys.,  1899,  Suppl.,  p.  289. 

Scheffer.    Arch.  f.  exp.  Path.  u.  Pharm.,  xliv,  p.  24. 

Hellsten.    Skand.  Arch.  f.  Phys.,  xvi,  p.  139;    xix,  p.  201. 

Dixon.    Journ.  of  Phys.,  xxv,  p.  346. 

Loeb.    Arch.  f.  exp.  Path.  u.  Pharm.,  iii,  p.  459. 

Kochmann.    Arch,  internal,  dc  pharmacodyn.,  xii,  p.  329. 

Bachcm.     Ibid.,  xiv,  p.  437. 

Schni/der.     Pfluger'.s  Archiv,  xciii,  p.  451. 

Roscninnn.     Pfliiger'.s  Archiv,  Ixxvii,  p.  405;    Ixxxvi,  p.  307. 

Neumann.    Arch.  f.  llyg.,  xxwi,  p.  1;  xii,  p.  S5. 

Atwater  and  Benedict.     V.  S.  Dept.  of  Agriculture  Exper.  Station  Hullctiii  No.  (ii). 

Ott.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlvii,  p    267. 

Qrchant.    Journ.  do  I'Anatoinio,  xxxvi,  p.  143. 


ETHER  AND  CHLOROFORM  195 

Abbott.    Journ.  of  Exp.  Med.,  i,  p.  477;   Univ.  of  Pennsylvania  Mod.  Bull.,  Sept.,  1902. 

Laitinen.     Ztschr.  f.  Hygiene,  xxxiv,  p.  206;    Iviii,  p.  139. 

Birch-Hirschfeld.    Arch.  f.  Ophthalmologie,  lii,  p.  358;   liv,  p.  68. 

Paton  and  Eason.    Jour,  of  Physiol.,  xxvi,  p.  166. 

Harrington.     Boston  Med.  and  Surg.  Journal,  1903.     (Germicidal  action.) 

Buller  and  Wood.    Journ.  of  Amer.  Med.  Assoc.,  1904,  ii. 

Brooks.    Journ.  Amer.  Med.  Assoc.,  1910,  ii,  p.  372. 

Mendel  and  Hilditch.    Amer.  Journ.  Physiol.,  xxvii,  p.  1. 

Sweisheimer .     Deutsch.  Arch.  f.  klin.  Med.,  cix,  p.  271. 

Voltz.    Arch.  f.  d.  ges.  Phys.,  cxxxviii,  p.  85;    cxlii,  p.  210;    cxlv,  p.  210. 

Togel,  Brezina,  and  Durig.     Biochem.  Ztschr.,  1,  p.  296. 

Dennig,  Hindelang,  and  Grunhaum.     Deutsch.  Arch.  f.  klin.  Med.,  xcvi,  p.  153. 

Mott.    Brit.  Med.  Journ.,  1911,  i,  p.  1381. 


2.  General  Anaesthetics — Ether  and  Chloroform. 

The  term  general  anaesthetics  is  employed  to  indicate  substances 
used  to  produce  unconsciousness  sufficiently  complete  to  allow  of  sur- 
gical operations  being  performed.  In  the  history  of  medicine  there 
are  repeatedly  abscure  allusions  to  substances  used  for  this  purpose,  but 
it  was  not  until  the  end  of  the  first  half  of  the  nineteenth  century  that 
the  era  of  surgical  aiiiesthesia  really  opened.  In  1798  Davy  advised 
the  use  of  nitrous  oxide  as  an  anaesthetic,  but  no  practical  use  was 
made  of  his  suggestion,  and  Wells  may  be  said  to  have  rediscovered 
this  property  of  the  gas  in  1844,  though  his  efforts  to  introduce  it  into 
general  use  met  with  no  greater  success  than  Davy's.  Long  used 
ether  in  1842-1843  in  surgical  operations,  but  did  not  give  any  pub- 
licity to  his  discovery,  and  the  honor  of  demonstrating  publicly  the 
practical  use  of  ether  in  surgery  must  be  awarded  to  Jackson  and 
Morton  in  1846.  In  1847  Simpson  introduced  chloroform  to  the 
medical  profession  as  a  substitute  for  ether,  over  which  he  supposed 
it  to  possess  several  advantages.  Its  pharmacological  action  had  been 
examined  some  months  earlier  by  Flourens,  but  Simpson  appears 
to  have  made  his  investigations  quite  independently.  Chloroform 
soon  ousted  ether  in  popular  favor  in  Europe,  and  although  in  America 
a  considerable  number  of  surgeons  continued  to  use  it,  ether  had  prac- 
tically fallen  into  complete  disuse  throughout  Europe,  save  in  Lyons, 
until  a  few  years  ago.  The  continually  increasing  number  of  accidents 
in  chloroform  anaesthesia  has,  however,  caused  a  reaction  to  set  in  in 
favor  of  ether,  and  it  seems  probable  that  it  will  once  more  be  reinstated 
as  the  rival,  and  perhaps  as  the  superior,  of  chloroform  throughout  the 
world.  Even  in  1880,  however,  Kappeler  could  write  that  in  (lermany 
chloroform  was  used  exclusively. 

Many  attempts  have  been  made  to  introduce  other  substances  of 
the  methane  series  as  substitutes  for  the  two  generally  recognized 
anaesthetics,  but  as  yet  no  other  has  attained  popular  favor.  Soon 
after  the  introduction  of  ether  and  chloroform,  nitrous  oxide  gained  a 
permanent  footing  as  an  anaesthetic  for  short  operations. 

These  anaesthetics  are  invariably  given  by  inhalation  and  not  by  the 
stomach,  as  it  is  found  that  the  exact  depth  of  the  narcosis  can  be 
much  more  easilv  controlled  bv  the  former  method.     Both  the  absorp- 


196  SUBSTANCES  ACTING  AFTER  ABSORPTION 

tion  and  excretion  of  these  drugs  occur  almost  entirely  by  the  lungs, 
according  to  the  ordinary  physical  laws  of  the  absorption  of  gases  by 
fluids.  The  more  concentrated  the  vapor  of  chloroform  in  the  lungs, 
the  greater  is  the  quantity  absorbed  into  the  blood  and  the  deeper  the 
narcosis.  By  regulating  the  proportion  of  the  vapors  in  the  air  in- 
haled, therefore,  an  anaesthesia  of  any  desired  depth  may  be  induced. 
The  degree  of  narcosis  and  of  danger  is  not  indicated  by  the  actual 
amount  of  the  anaesthetic  which  has  been  used,  but  by  the  concentra- 
tion of  the  vapors  which  have  been  inhaled;  one  patient  may  in  the 
course  of  a  long  operation,  inhale  and  again  exhale  many  ounces  of 
chloroform  without  danger,  while  another  may  be  thrown  into  a  position 
of  extreme  peril  by  the  inhalation  of  a  few  drops  of  chloroform  in  con- 
centrated vapor. 

Sjrmptoms. — The  action  of  chloroform  and  ether  may  be  divided 
into  three  stages:  (1)  that  of  imperfect  consciousness;  (2)  that  of 
excitement;  (.3)  that  of  anaesthesia. 

The  first  effect  of  their  application  is  a  feeling  of  asphyxia,  which  is 
especially  marked  in  the  case  of  ether,  and  of  warmth  of  the  face  and 
head  and  eventually  of  the  whole  body.  The  senses  become  less  acute, 
the  patient  seeming  to  see  only  through  a  veil  of  mist,  and  the  voices 
of  those  in  the  immediate  neighborhood  appearing  to  come  from  a 
distance.  Ringing,  hissing  and  roaring  in  the  ears  and  a  feeling  of 
stiffness  and  of  inability  to  move  the  limbs  herald  the  approach  of 
unconsciousness.  With  the  exception  of  the  first  feeling  of  suffocation, 
the  sensations  are  generally  pleasant.  During  this  stage  the  face  is 
generally  flushed,  the  pupils  enlarged,  the  pulse  is  somewhat  accelerated, 
and  the  respiration  may  be  rendered  irregular  by  the  sense  of  suflFocation, 
or  may  be  slightly  quickened.  Even  at  this  early  stage  sensation  is 
blunted. 

The  second  stage  of  excitement  varies  extremely  in  different  indi- 
viduals. In  some  cases,  especially  in  children,  it  is  entirely  absent, 
and  in  others  its  presence  may  be  indicated  merely  by  tremor,  by  the 
stretching  of  the  limbs,  or  by  irregularities  in  the  respiration,  but  in 
the  majority  of  cases  of  aniesthesia  it  is  much  more  marked.  It  often 
begins  by  movements  of  the  arms,  designed  either  to  push  away  the 
inhalation  mask  or  to  enable  the  patient  to  rise;  soon  his  other  muscles 
are  involved  in  the  movement;  he  struggles,  shouts,  sings,  groans, 
or  bursts  into  laughter.  The  movements  are  not  generally  uncoor- 
dinated, but  are  evidently  the  result  of  some  dream-like  condition  of 
the  consciousness,  and  these  dreams  are  often  connected  with  the 
operation  or  with  the  surroundings  of  the  patient  before  the  inhalation 
began.  They  are,  of  course,  determinod  largely  by  his  natural  mode 
of  thought — one  person  prays  aloud  and  sings  hymns;  another  abuses 
tlie  surgeon,  the.  liospital  and  all  his  recent  surroundings,  while  yet 
another  is  overcome  with  thf  fear  of  impending  death  and  laments 
his  uiifortunat<'  jxtsition.  In  this  stage  the  i)ulse  is  generally  cpiick- 
ened.  the  skin  is  (IusIkmI  and  often  cxanotic,  the  res])iration  is  (>xtremely 
irregular    from    tiic    struggling,  and    the    pupil  continues  somewhat 


ETHER  AND  CHLOROFORM  197 

dilated.  If  the  antTesthetic  be  pushed,  however,  the  movements  soon 
become  less  powerful,  the  muscles  relax  and  the  stage  of  anaesthesia 
sets  in. 

In  the  third  stage  the  face  assumes  a  calm,  death-like  appearance 
from  the  relaxation  of  the  muscles,  the  pupils  contract  somewhat  and 
do  not  react  to  light.  The  reflexes  disappear,  one  of  the  last  to  go 
being  the  closure  of  the  eyelids  on  touching  the  cornea.  The  pulse 
is  generally  somewhat  slow  and  weak;  the  face  is  pale  in  chloroform 
ansesthesia,  but  may  be  suffused  and  cyanotic  after  ether.  The  respira- 
tion is  slow  and  shallow,  but  regular.  This  stage  of  anaesthesia  may 
be  kept  up  for  hours  without  much  change  by  the  repeated  inhalation 
of  small  quantities,  although  the  pulse  tends  to  become  weaker  and 
the  respiration  shallower  unless  the  greatest  care  be  exercised,  and 
the  body  temperature  invariably  sinks.  When  the  administration 
ceases,  the  patient  passes  again  through  the  excitement  stage,  which, 
however,  is  not  generally  as  violent,  although  it  may  be  more  pro- 
longed, and  then  often  sinks  into  sleep,  which  lasts  several  hours. 
Not  infrequently,  however,  instead  of  sleep,  nausea,  giddiness  and 
vomiting  continue  for  some  time  after  the  recovery  of  consciousness. 

In  surgical  anaesthesia,  the  third  stage  is  often  interrupted  by  short 
intervals  of  semi-consciousness  and  slight  excitement  if  the  adminis- 
tration of  the  drug  be  interrupted  occasionally. 

The  use  of  these  drugs  is  so  widespread,  and  the  indications  of 
danger  in  anaesthesia  are  so  important  that  a  more  detailed  account 
of  the  alterations  observed  during  their  use  in  the  human  subject  may 
be  inserted  here. 

The  pulse  is  often  somewhat  accelerated  before  anaesthesia,  owning  to 
the  anxiety  and  nervousness  of  the  patient,  and  in  the  first,  and  still 
more  the  second  stage,  a  further  acceleration  may  occur  from  the  same 
cause,  although  in  other  instances  marked  slowing  of  the  pulse  may 
set  in  here  from  reflex  stimulation.  When  the  stage  of  anaesthesia  is 
reached,  the  pulse  becomes  slower  and  weaker  than  normally,  and  this 
change  increases  with  the  depth  of  the  anaesthesia  produced.  It 
remains  perfectly  regular,  however,  in  ordinary  cases,  and,  in  fact, 
unless  the  anaesthesia  has  reached  an  extremely  dangerous  stage.  In 
very  prolonged,  deep  anaesthesia  the  weakness  of  the  pulse  may  give 
rise  to  anxiety,  especially  if  the  temperature  of  the  body  is  very  low. 

The  respiration  is  generally  fairly  regular  until  the  second  stage, 
save  that  the  breath  may  be  held  for  some  time  owing  to  the  choking 
sensation,  and  a  deep  gasp  may  follow;  coughing  is  occasionally  met 
with,  especially  in  the  first  stage  of  ether  anaesthesia.  In  the  second 
stage,  the  respiration  is  extremely  irregular  when  the  excitement  is 
violent.  The  respiratory  muscles  are  involved  in  the  general  convul- 
sive movements,  so  that  no  air  whatever  can  enter  the  lungs  for  several 
moments,  and  then  several  deep  gasps  may  follow  and  load  the  blood 
with  concentrated  vapor.  During  the  third  stage  the  respiration 
becomes  regular  but  shallower  and  slower  than  before  the  anai'sthetic 
was  applied,  and  if  the  operation  be  prolonged,  the  weakness  of  the 


19S  SUBSTANCES  ACTING  AFTER  ABSORPTION 

respiration  may  give  rise  to  alarm.  Large  quantities  of  saliva  and 
mucus  may  hinder  the  respiration  and  require  removal,  and  a  common 
occurrence  is  the  production  of  snoring  from  the  falling  back  of  the 
tongue,  and  this  may  also  require  attention. 

The  behavior  of  the  pupil  is  of  some  imi)ortance  in  anaesthesia. 
During  the  first  and  second  stages  it  is  generally  somewhat  dilated, 
but  as  soon  as  complete  unconsciousness  is  attained,  it  becomes  rather 
narrower  than  it  is  normally.  As  the  patient  recovers,  the  slight 
dilatation  recurs,  and  if  the  respiration  and  circulation  be  danger- 
ously weak,  this  dilatation  also  occurs  in  most  cases.  Dilatation  of 
the  pupil  in  the  stage  of  anaesthesia,  therefore,  indicates  danger,  unless 
it  is  accompanied  by  symptoms  of  returning  consciousness,  such  as 
reflex  movements  and  vomiting. 

The  hypersecretion  of  saliva  and  of  bronchial  mucus  is  much  more 
marked  in  ether  than  in  chloroform  anaesthesia.  Vomiting  occurs  so 
frequently  during  anaesthesia  that  it  may  be  looked  upon  rather  as  one 
of  the  attendant  phenomena  than  as  an  accident.  It  may  set  in  prac- 
tically at  any  time,  but  is  more  often  seen  in  the  late  than  the  early 
stages,  and  more  frequetly  when  the  anaesthetic  is  applied  soon  after 
a  meal  than  when  the  stomach  is  empty. 

Action. — -The  action  of  ether  and  chloroform  on  the  Central  Nervous 
System  is  evidently  similar  to  that  of  alcohol,  although  the  })henomena 
habitually  elicited  in  the  use  of  the  former  are  very  rarely  produced 
by  the  latter.  In  all  three  intoxications,  however,  there  may  be  ob- 
served the  stages  of  lessened  consciousness,  of  excitement,  and  of  total 
unconsciousness.  Alcohol  was  formerly  administered  in  very  large 
quantities  to  allow  of  surgical  procedure,  and  ether  has  not  infrequently 
been  used  as  an  habitual  intoxicant. 

These  anaesthetics  produce  the  same  progressive  paralysis  of  the 
central  nervous  system  as  alcohol,  commencing  with  the  highest  cerebral 
functions,  those  of  self-control,  and  passing  downward  through  the 
lower  intracranial  divisions.  The  spinal  cord  is  att'ected  before  the 
medullar}'  centres,  which  are  the  last  part  of  the  central  nervous  system 
to  become  paralyzed.  The  question  arises  here,  as  under  alcohol, 
whether  a  stage  of  stimulation  does  not  precede  the  depression  of  the 
motor  functions,  and  it  is  certainly  difficult  to  believe  that  the  wild 
excitement  often  seen  in  the  second  stage  is  due  to  the  suppression 
of  the  self-control  only.  It  may  be  remarked  that  the  depression  of 
the  motor  areas  has  been  shown  experimentally  in  the  case  of  chloroform 
and  ether,  a  much  stronger  electric  stimulus  l)cing  necessary  to  produce 
movement  of  a  limb  after  these  drugs  than  before  them;  their  excita- 
bility by  the  electric  current  has  not  been  tested,  however,  during  the 
excitement  stage. 

The  anu'sthesia  is  not  j)r()(luccd  c(iually  rapidly  througliout  the 
body,  the  back  and  the  extremities  first  becoming  insensible,  then 
the  genital  organs  and  rectum  and,  last  of  all,  the  parts  supplied 
by  the  trigeminus.  The  reflexes  of  the  spinal  cord  are  depressed 
by  small  (luantities  of  ether  or  clilorot'orni  and  are  fiiKilly  paralyzed 


ETHER  AND  CHLOROFORM 


199 


Fig.  6 


completely.     The  character  of  the  reflex  is  changed,  for  Sherrington 
finds  that  stimulation  of  an  afferent  nerve  which  normally  causes  a 
reflex  contraction,  may  under  chloroform  be  followed  by  inhibition. 
A  similar  reversal    has    been  described  in 
the  medulla  oblongata  by  Bayliss. 

Both  of  the  anaesthetics  affect  the  sen- 
sory functions  before  the  motor,  as  is 
shoW'U  by  movements  occurring  long  after 
all  sensation  has  disappeared.  And  Bern- 
stein found  in  some  cases  that  if  chloroform 
was  excluded  from  an  area  of  the  spinal 
cord  by  destruction  of  part  of  the  pia 
mater,  reflexes  could  be  elicited  in  other 
parts  of  the  cord  by  the  irritation  of  sen- 
sory nerves  whose  cells  lay  in  the  protected 
area,  while  irritation  of  nerves,  the  cells  of 
which  w^ere  exposed  to  the  chloroform,  had 
no  effect  (Fig.  6).  In  the  protected  area 
there  were,  of  course,  both  motor  and 
sensory  cells,  and  an  impulse  reaching  the 
protected  sensory  cell  was  transmitted  to 
the  neighboring  and  also  to  more  distant 
motor  cells.  An  impulse  reaching  the 
exposed  sensory  cell,  on  the  other  hand, 

was  not  transmitted  to  the  motor  cells, 

although  these  were  shown   by  the  first 

part  of  the  experiment  to  be  capable  of 

stimulation.       This    experiment    is    best 

interpreted  by  supposing  that  the  anses- 

thetics  act  first  on  the  first  synapse  in  the 

cord  that  is  met  by  an  afferent  impulse. 

Later,  however,  the  motor  cells  or  their 

synapses  are  also  paralyzed,  as  is  shown 

by  stimulation  of  the  cord  having  no  effect, 

even  when  the  respiration  is  still  active. 
Electrical    stimulation   of    the    cerebral 

motor  areas  produces  movement  for  some 

time  after  sensation  has  been  lost,  but  as 

the  anaesthesia  becomes  deeper,  their  irri- 
tability disappears.    Finally  the  medullary 

centres  are   also   paralyzed  by  the  anses- 

thetic.    There  is  some  evidence  that  they 

are  first  stimulated  directly  by  chloroform 

and    ether    (page    200).      The    medullary 

centres  are  liable  to  be  affected  by  reflex 

stimulation  up  to  the  moment  at  which 

they  cease  to  send  out  impulses,  for  the 

respiratory  centre  responds  to  stimulation 


Diagram  of  the  spinal  cord: 
A-B  part  of  the  cord  exposed  to 
the  action  of  chloroform;  B-C 
part  unaffected.  A  sensory  im- 
pression traveling  by  the  pos- 
terior root  fibre  D  docs  not  elicit 
a  reflex  niovcmcnt,  but  one  reach- 
ing the  cord  through  the  unaf- 
fected root  E  causes  reflex 
impulses,  which  may  be  sent 
out  by  the  motor  cells  F,  F  in 
the  unaffected  area,  or  by  F',  F' 
in  the  poisoned  area.  The  ceils 
of  the  anterior  horns  F,  F'  and 
the  dendrites  surrounding  them 
are.  therefore,  intact  after  the 
reflex  arc  is  interrupted  at  some 
other  point. 


200 


SUBSTANCES  ACTING  AFTER  ABSORPTION 


of  the  superior  laryiio;eal  nerve  as  long  as  the  respiration  continues. 
It  is  possible  that  the  motor  cells  are  not  directly  paralyzed  by  the 
drug,  l)ut  can  only  send  out  impulses  received  from  the  sensory  cells, 
and  that  the  paralysis  of  these  is  the  cause  of  the  asphyxia. 

Shortly  stated,  the  direct  action  of  chloroform  and  ether  on  the  central 
nervous  system  is  a  descending  depression  and  paralysis  which  affects 
the  medullary  centres  last  of  all,  and  which  involves  the  synapses  on  the 
sensory  and  receptive  tracts  sooner  than  the  motor  neurons. 


Fig.  7 


Tracings  of  the  rcspiratiun  (uppor)  and  blood-pressure  (lower)  of  a  rabbit  at  the  begin- 
ning of  ether  inhalation,  which  is  indicated  by  the  arrow.  The  respiration  immediately 
becomes  very  shallow,  and  then  after  a  pause  becomes  slow  and  deep  (reflex  inhibition). 
The  blood-pressure  rises  and  the  pulse  is  slowed  by  reflexes  acting  on  the  vasomotor  and 
vagus  centres.  The  normal  condition  is  restored  at  once  when  the  ether  is  removed 
from  the  nose  at  A. 


The  action  of  chloroform  and  ether  on  the  Respiratory  Centre  is 
partly  direct  and  partly  indirect.  In  the  first  stage,  the  respiratory 
movements  may  be  slowed  or  stopped  temporarily  bj'  a  reflex  action 
set  up  by  the  irritation  of  the  terminations  of  tlie  trigeminus  in  the 
nose  and  throat  and  of  the  ])neumogastric  in  the  larynx  and  bronchi, 
but  this  interru|)ti<)n  is  only  of  short  duration  and  may  be  induced  by 
any  irritant  applied  to  the  res])iratory  passages  (Fig.  7).  During  the 
second  stage  the  respiration  is  often  rendered  irregular  by  the  convulsive 
struggHng,  wliich  produces  alternately  i)eriods  of  asph\xia  and  deep 
gasping  inoN'cnients.  'riierc  is  further  some  evidence  that  the  respiratory 
centre  is  rendered  more  irritable  b\-  low  concentrations  of  the  ana'stheties. 


ETHER  AND  CHLOROFORM  201 

more  especially  by  ether.  During  the  third  stage,  the  respiration  is 
regular  and  no  reflex  disturbance  occurs,  because  the  sensibility  is  so 
dulled  that  the  continued  irritation  of  the  nerve  ends  causes  no  reflex 
response.  In  this  stage  the  breathing  is  slow  and  shallow,  mainly  because 
the  ordinary  movements  of  the  body  are  suppressed  and  thus  less 
carbonic  acid  is  carried  to  the  centre,  that  is,  the  normal  stimulus  of 
the  respiratory  centre  is  diminished;  partly,  because  the  centre  is 
reduced  in  excitability  by  the  direct  action  of  the  anaesthetic.  If  the 
drug  be  pushed,  the  weakness  and  slowness  of  the  movements  increase, 
until  the  respiration  ceases  entirely  from  paralysis  of  the  centre;  in 
addition  to  its  direct  action  on  the  centre,  chloroform  affects  the 
respiration  in  deep  antesthesia  by  inducing  ansemia  of  the  medulla 
through  its  eft'ects  on  the  circulation. 

The  effects  of  the  anaesthetics  on  the  Circulation  are  extremely  com- 
plicated, because  the  heart,  the  medullary  centres  and  the  peripheral 
vessels  are  all  involved  in  the  action,  and  in  addition  the  changes  in 
the  respiration  and  the  stage  of  excitement  add  to  the  difficulty  of  the 
subject.  The  changes  observed  in  the  pulse  in  man  have  already  been 
described  (p.  197).  The  blood-pressure  in  man  has  been  found  to  be 
reduced  by  chloroform  even  in  the  earlier  stages,  and  in  deep  anaesthesia 
the  fall  may  be  very  marked.  Under  ether  the  pressure  rises  slightly 
in  the  first  and  second  stages,  partly  from  the  reflexes  arising  from  the 
local  irritation,  partly  from  the  muscular  movements,  and  partly 
perhaps  from  stimulation  of  the  vasomotor  centre.  During  complete 
anaesthesia  it  falls  again  to  slightly  above  the  normal  or  a  few  milli- 
meters below  it,  but  never  reaches  a  point  indicating  grave  circulatory 
disturbance  (Blauel,  Cook  and  Briggs). 

In  animals,  the  first  change  in  the  blood-pressure  is  often  a  slowing 
or  even  standstill  of  the  heart  from  the  irritation  of  the  air  passages 
stimulating  the  inhibitory  centre  reflexly.  The  blood-pressure  may 
thus  fall  abruptly,  but  in  other  instances  the  inhibition  of  the  heart 
may  be  compensated  by  vasoconstriction  from  reflex  stimulation  of  the 
vasomotor  centre,  so  that  the  blood-pressure  may  rise  while  the  heart  is 
slowed  (Fig.  7).  Later,  the  blood-pressure  falls  slightly  in  chloroform 
anaesthesia,  but  strong  vapor  causes  a  marked  and  dangerous  fall. 
The  heart  survives  after  the  respiration  fails  in  most  experiments  but 
the  blood-pressure  is  very  distinctly  lower  at  this  time  (Fig.  8).  Under 
ether  the  blood-pressure  often  is  slightly  lower,  but  it  remains  much 
higher  than  under  chloroform  when  the  respiration  fails  (Fig.  9).  The 
cause  of  the  fall  in  blood-pressure  under  chloroform  has  been  much 
disputed,  but  is  now  generally  ascribed  to  the  action  on  the  heart. 
Ether  being  less  poisonous  to  the  heart  has  a  correspondingly  slight 
action  on  the  blood-pressure. 

Heart.— The  frog's  heart  under  chloroform  or  ether  beats  more 
slowly  and  more  weakly,  and  at  the  same  time  undergoes  a  certain 
amount  of  dilatation,  all  owing  to  the  paralyzing  eftects  of  these  drugs 
on  the  cardiac  muscle. 

The  eftects  on  the  mammalian  heart  under  chloroform   are   \cTy 


202 


SUBSTANCES  ACTING  AFTER  ABSORPTION 


similar.    The  slowing  is  not  so  marked,  however,  as  the  weakness  and 
the  dilatation,  so  that  the  rhythm  of  the  pulse  does  not  indicate  the 


FiQ.  8 


The  respiration  (lower  tracing)  and  blood-pressure  (upper  tracing)  in  chloroform  anaes- 
thesia in  a  cat.  At  C  strong  vapor  was  inhaled  and  a  rapid  fall  in  the  blood-pressure 
began.  The  respiration  ceased,  the  heart  continuing  to  beat  for  some  time.  (Contrast 
Fig.  9.) 

extent  to  which  the  heart  is  affected.     The  auricles  are  weakened  b}' 
smaller  quantities  than   the   ventricles,  which  relax  more  completely 

Fig.  9 


Itr.-liiratioii  (Icnvfr  tracing)  and  l)l()()(l-prcssure  iuppcr  tracing)  of  a  cat  under  ether. 
.\t  J'J  strong  vapor  was  inhaled  and  soon  afterward  the  respiration  ceased,  while  the 
bIood-pre.ssurc  remained  high  for  some  time  afterward.  (Contrast  blood-pressure  in 
Fig.  8.) 

ill  diastole,  however  (Fig.  10).     The  diminution  in  the  strength  of  the 
auricles  progresses  rai)idl\',  while  the  ventricular  dilatation  soon  reaches 


ETHER  AND  CHLOROFORM 


203 


a  maximum  and  is  accompanied  by  lessened  force  of  contraction.  The 
auricular  weakness  soon  becomes  so  great  that  practically  no  blood  is 
expelled  by  its  systole,  and  the  slowing  of  the  heart,  which  has  not  been 
very  marked  up  to  this  point,  becomes  distinct.  The  ventricular  con- 
tractions next  become  extremely  weak  and  occasionally  fail  entirely, 
and  soon  afterward  the  heart  comes  to  a  standstill  in  diastole.  In 
its  weakened  state,  the  heart  can  be  inhibited  more  easily  than  usual, 
and  vagus  stimulation  may  arrest  it  finally,  the  contractions  not 
returning  after  the  stimulation  ceases  (Embley). 

When  ether  is  inhaled  in  high  concentrations  the  changes  in  the 
heart  resemble  those  under  chloroform,  but  it  is  difficult  to  elicit  the 
extreme  weakness  and  the  standstill  unless  asphyxia  is  present  also. 

Fig.  10 


Myocardiographic  record  of  the  movements  of  the  right  auricle  (upper  tracing)  and 
right  ventricle  (lower  tracing)  of  the  dog  during  the  inhalation  of  concentrated  chloro- 
form vapor.  During  systole  the  lever  attached  to  the  auricle  moves  from  D'  to  >S',  that 
attached  to  the  ventricle  from  D  to  S.  In  diastole  they  return  to  D'  and  D  respectively. 
At  ^4,  concentrated  chloroform  was  inhaled.  The  excursion  of  the  levers  toward  systole 
rapidly  diminished,  while  that  of  the  ventricle  towards  D  was  somewhat  augmented. 
After  a  short  time  the  auricle  ceased  in  diastole,  while  the  ventricle  continued  to  beat 
though  much  weakened.  At  B,  the  chloroform  was  shut  off  and  the  heart  began  to  recover 
very  soon  afterward. 


The  relative  toxicity  of  chloroform  and  ether  in  the  heart  has  been 
examined  by  perfusing  their  solutions  in  Ringer's  solution  through  the 
coronary  vessels;  0.001  per  cent,  of  chloroform  had  a  distinctly  delete- 
rious action  and  0.015  was  sufficient  to  arrest  it,  while  0.4  per  cent,  of 
ether  was  required  to  stop  the  heart  perfused  in  the  same  way.  This 
indicates  that  chloroform  is  25-30  times  as  poisonous  to  the  mammalian 
heart  as  ether;  the  same  proportion  has  been  found  in  cold-blooded 
animals. 

Vessels. — It  has  been  shown  experimentally  (daskell  and  Shore) 
that  the  vasomotor  centre  is  first  stimulated  by  chloroform,  but  this 
has  very  little  influence  on  the  calibre  of  the  bloodvessels  or  on  the 
arterial  pressure,  owing  to  the  direct  action  on  the  vessel  walls  and  heart. 
In  the  later  stages  the  vasoconstrictor  centre  undergoes  some  obscure 
change,  so  that  sensory  impulses  which  normally-  excite  it  and  cause 


204  SUBSTANCES  ACTING  AFTER  ABSORPTION 

constriction  of  the  vessels,  now  inhibit  it  and  canse  dilatation  of  the 
vessels  (Bayliss).  The  vasodilator  centre  continues  to  respond  in  its 
normal  way  to  sensory  impulses.  Ether  seems  to  have  little  or  no 
direct  action  on  the  vaso-constrictor  centre,  but  the  dilatation  of  the 
skin  vessels  indicates  that  it  excites  the  vasodilator  function. 

The  direct  action  on  the  vessel  walls  seems  to  be  of  greater  impor- 
tance than  that  on  the  innervating  centres.  When  chloroform  circu- 
lates in  the  vessels  in  the  concentrations  used  in  anaesthesia  it  tends 
to  relax  them  from  a  depressing  effect  on  the  muscle  fibres;  all  the 
vessels  are  not  equally  affected,  however,  those  of  the  splanchnic  area 
dilating  more  readily  than  those  of  the  limbs,  which  may  even  be  con- 
stricted. Chloroform  in  higher  concentration  may  tend  to  constrict 
also  the  mesenteric  vessels,  but  this  does  not  occur  in  the  intact  animal, 
in  which  such  concentrations  would  prove  immediately  fatal  to  the  heart. 

In  practice,  the  low  blood-pressure  under  chloroform  is  mainly  due 
to  the  action  on  the  heart;  in  less  degree  to  the  dilatation  of  the  vessels 
in  the  abdomen. 

Ether  dilates  the  peripheral  vessels  like  chloroform  wdien  it  is  perfused 
through  them,  and  if  it  is  inhaled  in  abundance  of  air  this  dilatation 
occurs  in  the  living  animal  and  may  cause  a  fall  in  blood-pressure.  This 
is  often  absent  however,  because  the  direct  vascular  action  is  opposed 
by  the  vasomotor  centre  which  is  excited  by  an  insufficient  air  supply; 
for  in  ether  anaesthesia  there  is  very  often  present  a  partial  asphyxia 
induced  by  the  close  approximation  of  the  inhaler  to  the  mouth  and 
nose. 

Syncope  in  Anaesthesia. — In  a  certain  number  of  experiments  the 
reaction  of  the  circulation  to  chloroform  is  very  different  from  the  gradual 
depression  described  above.  In  these,  the  heart  suddenly  becomes 
irregular  or  ceases  to  beat  abruptly,  the  blood-pressure  falls  to  zero, 
and  after  a  few  gasping  respirations  all  movements  cease  (Fig.  11). 
This  sudden  heart  failure  often  occurs  in  the  early  stages  of  anaesthesia, 
or  when  the  inhalation  is  irregular  or  has  been  suspended.  Embley 
has  explained  it  by  inhibitory  stimulation  from  which  the  weakened 
heart  cannot  recover.  But  Levy  attributes  it  to  the  onset  of  ventricular 
fibrillation  and  has  brought  a  large  amount  of  evidence  for  his  view. 
This  fibrillation  is  often  the  culmination  of  a  series  of  irregularities, 
such  as  extrasystoles  and  tachycardia,  but  may  not  be  i)receded  by  these 
in  all  cases.  It  indicates  a  condition  of  abnormal  irritability  of  the 
heart  under  chloroform,  and  other  experiments  have  given  some  evidence 
for  a  phase  of  increased  excitability  preceding  the  depression  ordinarily 
observed.  This  form  of  cardiac  failure  is  very  often  final,  but  in  a  small 
proportion  of  cases  the  heart  resumes  its  normal  contractions  and  the 
animal  recovers.  Fibrillation  is  especially  liable  to  occur  from  sensory 
nerve  stimulation  during  light  ana'sthesia,  and  it  is  possible  that  here 
the  excitatory  effect  on  the  heart  is  reinforced  by  reflexes  through  the 
accelerator  apparatus  or  by  an  increased  secretion  of  the  suprarenal 
glands.  It  is  not  proved  that  the  inhibitory  nerves  are  involved  in  this 
loriM  of  heart  failure,  though  there  is  some  evidence  in  favor  of  this  view. 


ETHER  AND  CULOliOFORM 


205 


Fig.   11 


Ether  does  not  seem  to  have  any  such  action  on  the  heart,  and  fibrilla- 
tion of  the  ventricle  has  not  been  observed  under  it.  In  fact,  sudden 
circulatory  failure  under  ether  is  a  very  rare  occurrence,  compared 
with  chloroform.  Henderson  suggests  that  these  rare  fatalities  under 
ether  may  be  the  result  of  a  great  reduction  of  the  carbonic  acid  of  the 
blood  (acapnia),  from  excessive  breathing  during  the  excitement  stage  or 
during  imperfect  anjesthesia.  Acapnia  is 
known  to  act  deleteriously  on  the  heart,  but 
further  work  is  required  before  this  view  of 
the  fatalities  under  ether  can  be  regarded  as 
established. 


The  Muscles  and  Nerves  are  not  affected  by 
chloroform  or  ether  when  inhaled,  but  when  a 
frog's  muscle  is  exposed  to  an  atmosphere  of  either 
of  them,  it  is  weakened,  loses  its  irritability  and 
eventually  passes  into  rigor  mortis;  the  limb  mus- 
cles in  mammals  are  weakened  when  strong  solutions 
(0.1-0.2  per  cent.)  are  perfused  through  them,  but 
are  unaffected  by  concentrations  which  arrest  the 
heart  in  a  few  minutes.  Waller  has  shown  that 
when  a  frog's  nerve  is  exposed  to  chloroform  or 
ether  vapor  in  weak  dilution,  its  irritability  is  at 
first  increased;  strong  vapor,  on  the  other  hand, 
abolishes  the  excitability  temporarily  in  the  case 
of  ether,  generally  permanently  in  that  of  chloro- 
form, which  is  much  the  more  powerful  nerve 
poison  of  the  two.  The  sensory  fibres  are  said  to 
be  paralyzed  sooner  than  the  motor  when  chloro- 
form or  "ether  is  applied  to  a  mixed  nerve  (Pereles 
and  Sachs),  and  some  motor  fibres  of  a  trunk  may 
remain  unaffected,  while  others  are  paralyzed.  The 
local  paralyzing  effects  of  ether  have  been  elicited 
repeatedly  in  the  human  subject  by  its  subcu- 
taneous injection,  and  have  occasionally  been  fol- 
lowed by  neuritis  and  permanent  weakness. 


I'lariiiL;  (if  the  blood-press- 
ure (lower)  aud  of  the  respi- 
ration (upper)  of  a  cat  under 
chloroform;  failure  of  the 
heart  (ventricular  fibrilla- 
tion) immediately  after  vio- 
lent struggling.  The  blood- 
pressure  falls  rapidly,  while 
deep,  gasping  respiration  con- 
tinues for  a  short  time  and 
then  ceases.     (Levy.) 


Chloroform  and  ether  dissolve  the  Red 
Corpuscles  and  free  the  haemoglobin  when 
they  are  shaken  with.defibrinated  blood  out- 
side the  body,  and  chloroform  is  said  to 
retard  the  reduction  of  oxyhemoglobin  by  forming  a  loose  combination 
with  it;  Da  Costa  holds  that  ether  tends  to  destroy  the  red  cells  during 
anaesthesia,  and  advises  caution  in  its  administration  in  cases  in  which 
a  diminution  in  their  numbers  may  be  of  serious  import.  In  the  blood, 
chloroform  is  carried  by  the  red  cells  for  the  most  part,  less  than  10  per 
cent.,  being  free  in  the  plasma.  It  appears  to  form  a  loose  combina- 
tion or  solution  in  the  cholesterin  and  lecithin  of  the  corpuscles.  Ether 
is  said  to  l)e  more  equally  distri})uted  between  the  corpuscles  and  plasma. 

The  amount  of  chloroform  in  the  blood  during  the  stage  of  ana«sthesia 
is  about  25-35  mgs.  in  100  c.c.  When  the  respiration  fails  the  blood 
is  found  to  contain  40-70  mg.  per  100  c.c.  (Buckmaster  and  Gardner). 


206  SUBSTANCES  ACTING  AFTER  ABSORPTION 

Diirino;  the  induction  of  antiesthesia  the  arterial  blood  contains  more 
than  the  venous,  part  of  the  chloroform  being  taken  up  by  the  tissues 
as  it  passes  through  the  capillaries.  On  the  other  hand,  as  the  anaesthesia 
passes  off,  the  venous  blood  contains  more  than  the  arterial,  the  anses- 
thetic  taken  up  from  the  tissues  in  the  capillaries  being  eliminated 
in  the  lungs.  Nicloux  states  that  in  light  antesthesia  from  ether  the 
blood  contains  about  100-110  mgs.  per  100  c.c,  in  deep  ansesthesia 
130-140  mgs.,  while  160-170  mgs.  per  100  c.c.  proves  fatal  from  failure 
of  the  respiration.  The  margin  of  safety  in  antesthesia  is  thus  narrower 
than  is  generally  recognized,  for  the  concentration  in  the  blood  necessary 
for  anaesthesia  is  about  half  that  which  is  fatal. 

The  effects  of  chloroform  and  ether  on  the  Pupil  present  some  varia- 
tion in  different  animals,  and,  indeed,  are  not  very  constant  in  man. 
No  entirely  satisfactory  explanation  of  their  mechanism  has  been 
offered  as  yet.  The  dilatation  of  the  pupils  in  the  first  and  second 
stages  is  merely  the  accompaniment  of  the  general  excitement  and 
anxiety,  and  is  not  specific.  The  contraction  in  the  stage  of  uncon- 
sciousness is  similar  to  that  seen  in  natural  sleep,  and  is  evidently  of 
central  origin.  The  dilatation  occurring  during  wakening  or  vomiting 
is  evidently  caused  by  the  same  process  as  that  of  the  preliminary 
stages.  Just  before  death  the  pupil  dilates,  and  this  may  perhaps  be 
attributed  to  the  effects  of  asphyxia  on  the  muscle  of  the  iris,  and  is 
so  frequently  observed  in  death  from  other  causes  that  it  cannot  be 
regarded  as  a  direct  result  of  the  chloroform. 

The  local  effects  of  the  anaesthetics  on  the  Alimentary  Canal  and 
Respiratory  Passages  are  confined  to  irritation  with  resultant  reflexes. 
Thus  the  profuse  secretion  of  saliva  and  of  mucus  is  due  to  the  irri- 
tation causing  increased  activity  of  the  glands  reflexly,  and  can  be 
arrested  by  atropine.  It  has  been  stated  that  the  bronchial  rhonchi 
are  due  entirely  to  aspirated  saliva,  but  this  is  incorrect,  as  they  occur 
in  animals  to  which  the  anaesthetic  has  been  given  through  a  tracheal 
cannula.  The  irritation  is  much  greater  when  concentrated  ether 
fumes  are  inhaled  than  in  ordinary  chloroform  anivsthesia. 

Tlie  vomiting  which  is  so  often  a  feature  of  anaesthesia  may  arise 
in  part  from  the  irritating  action  on  the  stomach  of  the  chloroform 
or  ether  swallowed  in  the  mucus,  but  is  probably  partly  of  central  origin, 
for  vomiting  also  occurs  when  ether  is  injected  intra\enously  in  man 
and  also  under  nitrous  oxide  ana'sthesia  in  some  cases;  here  the  local 
irritation  can  only  plaj^  a  small  part,  and  the  medullary  centre  is  prob- 
ably involved  directly.  The  ordinary  movements  of  the  stomach 
and  intestine  do  not  seem  to  be  influenced  l)y  aiia'sthesia,  unless  when 
it  is  a('(()ni));inicd  })y  ;is])hyxia,  when  the  peristalsis  may  be  increased. 

The  Kidney  a|)i)ears  to  be  allected  in  a  certain  i)r()p()rtion  of  cases 
of  ana'sthesia  in  man,  as  is  shown  by  (he  ai)pcarance  of  albumin  in  the 
urine.  (Milorofonn  induces  t\pical  fatty  degeneration  occasionally, 
while  albuminuria  has  been  observed  in  a  certain  proportion  of  cases 
afti-r  ctlicr.  The  ])roportioii  of  easels  in  which  this  organ  is  allected 
s«<'ins   to   \ar\'   extraordinariK ,   some  authorities  Hndinii-  albuminuria 


ETHER  AND  CHLOROFORM  207 

in  30  per  cent,  of  the  cases  where  chloroform  was  used;  while  others 
could  detect  it  in  less  than  8  per  cent.  Kemp  ascribes  the  renal  eft'ects 
of  ether  to  vasoconstriction,  but  this  is  not  an  immediate  action  of 
ether,  but  arises  from  partial  asphyxia  from  the  inhaler  beipg  applied 
too  closely;  when  asphyxiation  is  avoided,  albuminuria  is  hardly  met 
with  under  ether,  and  most  surgeons  consider  chloroform  far  more 
deleterious  to  the  kidney.  The  secretion  of  urine  is  generally  diminished 
during  anaesthesia  with  chloroform  or  ether,  from  the  reduced  blood- 
pressure  and  imperfect  aeration  of  the  blood.  After  recovery  from  ether 
aniaesthesia  some  diuresis  may  occur,  or  the  urine  may  remain  scanty 
for  some  hours. 

The  Uterine  Contractions  during  parturition  seem  little  influenced 
by  moderate  anaesthesia,  but  are  somewhat  slowed  in  the  deeper  stages. 
Chloroform  and  ether  pass  into  the  foetal  blood,  and  some  experi- 
ments are  recorded  in  which  the  foetus  was  killed  by  the  inhalation, 
while  the  mother  recovered.  This  may  be  caused  either  by  the  direct 
action  of  the  drug  on  the  young  animal,  or  by  the  low  maternal  blood- 
pressure  leading  to  its  asph;^Tiia.  It  does  not  seem  dangerous  to 
induce  a  moderate  degree  of  anaesthesia  during  labor  in  human  beings, 
although  here,  too,  the  effects  on  the  child  are  shown  by  an  increase 
in  the  nitrogen  excretion  in  the  urine  for  some  da}'s;  some  authorities 
attribute  many  of  the  diseases  of  the  first  days  of  life  to  the  use  of 
chloroform  during  labor,  but  the  evidence  is  not  convincing. 

The  Temperature  falls  during  anaesthesia  of  even  short  duration. 
Thus  Kappeler  found  it  reduced  0.2-1.1°  C.  when  chloroform  was 
inhaled  15-40  minutes,  and  a  fall  of  3-5°  C.  has  been  observed  during 
very  long  anaesthesia.  This  action  is  due  partly  to  the  greater  output 
of  heat  through  the  dilated  skin  vessels,  but  mainly  to  lessened  heat 
production  from  the  diminished  muscular  movement.  It  is  not  neces- 
sary to  assume,  therefore,  as  some  writers  do,  that  the  anaesthetics  lessen 
the  heat  production  by  their  direct  effects  on  the  tissues  in  general. 

Of  late  years  a  good  deal  of  interest  has  been  manifested  in  the 
effects  of  the  anaesthetics  on  the  Metabolism  of  the  tissues,  and  it  is  now 
generally  recognized  that  chloroform,  in  addition  to  its  action  on  the 
central  nervous  system,  produces  marked  changes  in  the  nutritive 
processes  of  protoplasm.  The  simpler  organisms,  which  are  devoid 
of  nervous  structure,  are  killed  in  comparatively  dilute  solutions,  and 
chloroform  water,  therefore,  prevents  or  retards  putrefaction  and  the 
fermentation  of  yeasts.  It  seems  to  hinder  the  action  of  some  fer- 
ments, such  as  pepsin  and  rennet  ferment,  when  added  in  compara- 
tively large  quantities,  but  increases  their  activity  in  greater  dilution. 
Plants  cease  to  assimilate  carbonic  acid,  but  are  not  killed  by  chloro- 
form except  in  very  large  quantities.  In  the  higher  animals  and  in  man, 
the  processes  of  life  and  nutrition  of  the  different  organs  also  undergo 
alteration,  quite  apart  from  the  effects  on  the  nervous  system.  Thus  fatty 
infiltration  of  various  organs  is  produced  by  chloroform  administered 
repeatedly  and  even  by  a  single  inhalation  in  some  cases.  The  organs 
implicated  in  this  change  are  the  liver,  heart  and  kidneys  more  espe- 


208  SUBSTANCES  ACTING  AFTER  ABSORPTION 

cially,  but  cle<i:;eneration  of  ordinary  muscle  has  also  been  observed  occa- 
sionally. If  this  process  attains  a  certain  degree  of  development,  it  may 
lead  to  failure  of  the  heart,  but  otherwise  the  tissues  recover  in  the 
course  of  a  few  days.  Traces  of  fatty  infiltration  have  been  observed 
after  prolonged  ether  narcosis  also,  but  they  are  so  slight  that  no  sig- 
nificance attaches  to  them  from  a  practical  point  of  view  (Selbach). 
Given  in  small  quantities  for  several  months,  chloroform  leads  to  atrophic 
cirrhosis  of  the  liver,  and,  to  a  less  extent,  of  the  kidneys,  spleen  and 
lungs,  this  cirrhotic  change  forming  a  sequel  to  preliminary  fatty  changes 
of  the  parenchymatous  cells.  In  young  adults  chloroform  has  occasion- 
ally given  rise  to  a  form  of  liver  afl'ection  which  closely  resembles 
acute  yellow  atrophy.  In  these  cases  after  recovery  from  the  anaes- 
thetic, the  patient  becomes  restless  and  uneasy  and  in  a  few  hours 
delirium  and  coma  may  appear.  Jaundice,  cutaneous  haemorrhages 
(from  a  diminished  amount  of  fibrinogen  in  the  blood),  tenderness  over 
the  liver  suggest  an  affection  of  this  organ,  and  in  fatal  cases  it  is 
found  to  present  the  same  appearance  as  in  acute  yellow  atrophy,  the 
cells  in  the  centre  of  the  lobules  having  undergone  necrosis;  chemical 
examination  proves  that  an  acute  autolytic  destruction  of  the  organ 
has  occurred  (Wells).  In  animals  this  necrosis  is  less  liable  to  occur 
if  the  diet  previously  has  been  rich  in  carbohydrates,  while  fats  seem 
to  predispose  to  it. 

The  effects  of  chloroform  on  the  nutrition  of  the  tissues  are  shown 
in  the  urine  secreted  during  and  after  aniiesthesia,  though  they  are 
more  marked  when  the  drug  is  swallowed,  from  its  being  more  slowly 
absorbed  and  thus  acting  for  a  longer  time.  The  nitrogen  eliminated 
is  considerably  increased,  and  the  unoxidized  sulphur  shows  a  similar 
augmentation,  and  these  would  seem  to  indicate  an  increased  protein 
destruction  and  a  disturbance  of  the  oxidation  in  the  tissues;  another 
observation  pointing  in  the  same  direction  is  the  appearance  of  creatin 
in  the  urine  and  the  reduced  excretion  of  creatinin. 

The  carbohydrate  metabolism  is  also  impaired,  for  acetone  and  sugar 
are  often  present  in  the  urine  after  chloroform,  and  it  has  long  been 
known  that  diabetes  is  liable  to  be  aggravated  by  this  anjesthetic 
and  may  prove  fatal.  The  sugar  of  the  blood  is  increased  and  the 
glycogen  of  the  liver  diminished  or  absent,  from  a  specific  action  on  the 
liver  cells  (Paton). 

Bile  j)igment  is  said  to  occur  in  the  urine  in  a  considerable  number 
of  cases  of  ana'sthesia  with  chloroform,  especially  one  or  two  days 
after  the  administration.  The  chlorides  and  the  acidity  of  the  urine  are 
augmented  and  this  has  sometimes  been  regarded  as  evidence  that 
chloroform  is  decomposed  in  the  tissues,  but  the  chlorides  are  also 
increased  by  ctlicr  though  not  in  the  same  degree. 

These  cH'ccts  of  chloroform  on  the  metabolism  resemble  very  closely 
those  of  phosphorus  poisoning,  ;ind  have,  like  them,  been  ascribed  to 
autolysis  and  the  formation  of  acid  in  excess  in  the  tissues.  They 
scciu  to  occur  only  after  those  substances  of  the  fatty  series  in  which 
chlorine  is  substituted,  ether  ha\"ing  little  or  no  effect  in  prtxlucing 


ETHER  AND  CHLOROFORM  20!) 

fatty  degeneration  or  in  changing  the  proportion  of  tiie  sulphur  coui- 
pounds  in  the  nrine.  An  excess  of  sugar  is  found  in  the  blood  after 
ether  amesthesia  in  dogs  and  leads  to  glycosuria;  this  is  due  to  changes 
in  the  liver,  but  probably  arises  from  partial  asphyxia  during  the  inlia- 
lation  and  not  from  any  direct  action  of  the  ether  on  the  metabolism 
(Hawk). 

Immunity.— Anaesthesia  with  chloroform  or  ether  reduces  the  resist- 
ance of  the  tissues  and  renders  animals  more  susceptible  to  the  invasion 
of  bacteria  and  to  the  action  of  toxins. 

Distribution  in  the  Body. — When  chloroform  or  ether  vapor  is  inhaled, 
it  passes  rapidly  into  the  blood  by  diffusion  and  is  distributed  through- 
out the  body,  mainly  by  the  blood  cells  in  the  case  of  chloroform,  while 
the  plasma  carries  a  considerable  amount  of  ether.  The  antesthetic 
immediately  begins  to  leave  the  blood  for  the  tissues  and  appears  to  be 
taken  up  especially  by  the  central  nervous  system,  in  which  it  is  found 
in  larger  quantities  than  in  the  muscles,  liver,  or  blood.  This  unequal 
distribution  probably  arises  from  the  greater  amount  of  lipoid  substances 
in  the  central  nervous  system,  which  dissolve  the  chloroform  and  ether 
and  retain  them.  This  flow  from  the  pulmonary  alveoli  to  the  blood 
and  thence  to  the  tissues  lasts  until  the  vapor  tension  is  the  same  in 
each,  and  the  amount  in  the  brain  is  thus  determined  by  that  in  the 
blood,  which  again  depends  on  that  in  the  alveoli.  If  the  inhalation 
ceases,  the  tension  in  the  lungs  falls  and  a  backward  flow  follows  from 
the  blood  into  the  air  and  from  the  brain  into  the  blood. 

The  Excretion  of  both  ether  and  chloroform  takes  place  mainly  l)y 
the  lungs.  ]Most  of  the  anaesthetic  is  eliminated  very  rapidly,  but 
traces  of  chloroform  are  said  to  be  found  in  the  breath  for  twenty-four 
hours  after  the  inhalation  and  even  longer  in  cases  in  which  there  is  a 
tenacious  mucous  secretion  from  the  bronchi.  x\s  far  as  is  known  this  is 
the  only  way  in  which  ether  is  excreted,  but  small  quantities  of  chloro- 
form escape  by  other  channels,  for  it  has  been  found  in  the  urine,  and 
is  said  to  occur  in  the  perspiration  and  the  milk.^ 

Differences  Between  Chloroform  and  Ether. — Ether  and  chloroform 
resemble  each  other  closely  in  their  general  effects,  but  differ  in  power 
and  in  other  points  of  importance.  Their  relative  strength  as  anies- 
thetics  is  shown  by  a  comparison  of  the  vapor  concentration  of  each 
in  a  hundred  volumes  of  air  required  to  induce  anaesthesia. 

Chloroform.  Ether. 

0.5-0.7  1.5-2.5  Insufficient  to  cause  anaesthesia. 

1.0  3-3.5  Causes  anaesthesia  on  prolonged  inhalation. 

2.0  6.0  Arrests  respiration  after  some  time. 

The  amount  of  anesthetic  in  100  c.c  of  the  blood  shows  the  same 
proportion. 

Chloroform.  Ether. 

25-35  mgs.  100-140  mgs.  Anaesthesia. 

40-70  mgs.  160-170  mgs.  Respiratory  arrest. 

1  The  statement  that  some  carbon  monoxide  is  formed  in  the  tissues  from  the  oxi- 
dation of  chloroform  is  erroneous. 
14 


210  SUBSTANCES  ACTING  AFTER  ABSORPTION 

The  depressant  effect  of  chloroform  on  the  brain  is  thus  3-3|  times 
as  great  as  that  of  ether,  and  its  power  to  arrest  respiration  is  about 
three  times  as  great.  The  depressant  action  on  the  heart  of  chloroform  is 
about  25-30  times  that  of  ether,  and  the  extremely  dangerous  cardiac 
syncope  which  is  seen  under  chloroform  is  very  rare  under  ether.  Ether 
has  to  be  given  in  more  concentrated  form  to  produce  anjesthesia,  and, 
therefore,  produces  more  irritation  of  the  air  passages,  as  showTi  by  the 
greater  secretion  of  saliva  and  mucus,  by  coughing,  and  by  the  sensa- 
tion of  asphyxia.  Anaesthesia  is  produced  with  greater  difficulty,  more 
slowly  and  often  less  perfectly  than  with  chloroform,  and  the  stage  of 
excitement  is  generally  more  violent  and  prolonged.  But  the  pulse  is 
not  nearly  so  much  affected  as  by  chloroform;  it  may  be  somewhat 
slower  than  usual,  but  is  fiill  and  strong.  The  concentration  of  chloro- 
form which  is  necessary  to  produce  anaesthesia  is  very  close  to  the  con- 
centration which  causes  serious  impairment  of  the  heart's  action,  while, 
on  the  other  hand,  3|  per  cent,  ether  vapor  is  sufficient  to  maintain 
narcosis,  but  a  very  much  stronger  concentration  is  required  to  cause  a 
dangerous  condition  of  the  heart.  In  the  same  way,  the  difference  in 
the  concentration  required  to  produce  anaesthesia  and  that  which  will 
stop  the  respiration  is  smaller  in  chloroform  than  in  ether,  and  the 
anaesthetist  has  thus  more  leeway  when  he  uses  the  latter.  The  changes 
in  the  metabolism  following  the  use  of  chloroform  are  not  produced 
to  the  same  extent,  if  at  all,  by  ether. 

Regarding  the  Choice  of  an  Anaesthetic,  it  must  be  said  that  each  has 
its  advantages,  but  that  ether  is  less  liable  to  cause  dangerous  symp- 
toms than  chloroform,  and  ought,  therefore,  to  be  used  wherever  special 
circumstances  do  not  indicate  the  latter.  Chloroform  is  always  pre- 
ferred by  the  patient,  for  it  causes  less  irritation  and  less  feeling  of 
suffocation,  and  it  is  often  preferred  by  the  surgeon  because  it  induces 
anaesthesia  sooner  and  less  of  it  is  required.  In  cases  where  excite- 
ment is  to  be  avoided  as  much  as  possible,  or  in  which  very  deep 
anaesthesia  with  complete  muscular  relaxation  is  required,  and  in  irri- 
table conditions  of  the  air  passages,  chloroform  ought  to  be  used  rather 
than  ether.  In  drunkards,  ether  sometimes  fails  to  induce  deep  anaes- 
thesia, and  in  very  hot  climates  anjesthesia  with  ether  may  be  difficult 
and  unpleasant  to  induce  owing  to  its  rapid  evaporation,  so  that  in 
these  cases  chloroform  may  be  necessary.  Lastly,  where  artificial  lights 
are  necessary  (except  the  electric  incandescent),  or  where  the  actual 
cautery  is  to  be  used,  ether  is  dangerous  on  accoimt  of  its  inflammability, 
and  chloroform  is  indicated.  On  the  other  hand,  chloroform  is  specially 
contra-indicated  in  cases  of  fatty  change  of  the  heart  and  in  renal  disease, 
'i'hc  disadvantages  of  both  anjcsthetics  may  often  be  avoided  by  inducing 
unconsciousness  by  chloroform  and  prolonging  it  by  small  quantities 
of  ether.  The  effects  of  the  prolonged  use  of  chloroform  are  avoided 
in  this  way,  and  at  the  same  time  the  excitement  is  less  marked,  and  less 
irritation  of  the  air  passages  is  elicited  than  if  the  anaesthesia  had  been 
induced  by  concentrated  ether  vapor. 


ETHER  AND  CHLOROFORM  211 

The  Dangers  of  Anaesthesia  are  caused  only  in  part  by  the  direct 
action  of  the  ether  or  chloroform,  for  fatal  accidents  have  occurred 
from  objects  such  as  false  teeth  or  tobacco  plugs  falling  into  the  air 
passages  and  causing  asphyxia,  while  vomited  matter  has  been  drawn 
into  the  larynx  in  some  cases.  Very  often  the  relaxation  of  its  muscles 
permits  the  tongue  to  fall  back  into  the  throat,  rendering  the  breathing 
labored  and  stertorous;  this  is  at  once  relieved  when  the  tongue  is 
drawn  forward.  The  accumulation  of  saliva  and  mucus  or  blood  in  the 
throat  may  lead  to  similar  symptoms.  In  these  accidents  the  chloroform 
or  ether  is  only  indirectly  the  cause,  but  in  a  large  and  ever-increasing 
number  of  cases,  the  fatal  effects  must  be  ascribed  to  the  direct  action 
of  the  anaesthetics.  The  proportion  of  accidents  during  anaesthesia  is 
very  difficult  to  estimate,  and  great  discrepancies  occur  in  the  statistics 
of  different  surgeons.  Thus,  in  one  of  the  London  hospitals,  one  death 
occurred  from  chloroform  in  1236  cases  of  anaesthesia;  Juillard  gives 
one  in  3258,  McGuire  one  in  15,000,  as  the  proportion  of  fatalities, 
while  Lawrie  gives  a  series  of  over  40,000  cases  w^ithout  a  single  death. 
A  fair  average  would  seem  to  be  one  death  in  3000  chloroform  inhala- 
tions. The  statistics  of  ether  fatalities  also  vary  from  one  death  in 
3000  to  one  in  16,000  cases,  but  probably  one  in  10,000-12,000  cases 
would  represent  the  average  mortality.^ 

The  Cause  of  Death  in  anaesthesia  has  been  a  subject  of  discussion 
for  over  fifty  years,  and  it  is  only  now  being  recognized  that  there  are 
at  least  two  different  forms  of  fatality  which  may  occur.  The  first 
of  these  may  be  termed  Cardiac  Syncope,  and  occurs  chiefly  in  chloro- 
form anaesthesia,  to  which  it  contributes  the  greater  part  of  the  fatali- 
ties. In  these  cases  it  is  generally  stated  that  the  pulse  suddenly 
disappears,  the  patient's  face  assumes  a  death-like  pallor,  the  reflexes 
fail  and  the  pupils  dilate.  The  breathing  suddenly  becomes  deep  and 
labored  (this  often  being  the  first  symptom  observed)  and  ceases  after 
a  short  time.  This  accident  is  generally  stated  to  occur  in  the  early 
stages  of  anaesthesia,  often  before  the  operation  has  begun,  but  it  is  also 
met  with  after  vomiting  and  other  interruptions  to  a  smooth  course  of 
anaesthesia.  No  explanation  of  the  fatality  was  given  until  Embley's 
and  Levy's  researches  on  animals  showed  that  a  similar  sudden  heart 
failure  may  be  observed  experimentally.  Embley  regards  these  accidents 
as  the  result  of  excessive  and  abnormal  inhibitory  activity,  and  it  is  not 
impossible  that  the  inhibitory  apparatus  may  be  involved  in  some  of 
them.  But  Levy's  explanation  (p.  204)  that  the  ventricle  passes  into 
fibrillation  is  more  satisfactory  and  more  in  accordance  with  the  clinical 
observations.  The  conditions  which  favor  the  onset  of  this  condition 
are  still  obscure.  Imperfect  anaesthesia  is  obviously  one  of  them, 
but  this  may  conduce  to  the  fibrillation  either  through  permitting 
reflexes  to  act  on  the  heart,  or  by  throwing  that  organ  into  the  state  of 
irritability  in  which  fibrillation  is  liable  to  occur.     Fibrillation  has  not 

'  Gurlt's  careful  statistics  of  330,000  cases  of  ansesthcsia  gave  a  nioitality  of  1  in  2000 
for  chloroform  and  1  in  5000  for  ether,  but  these  both  seem  unusually  high. 


212  SUBSTANCES  ACTIXC   AFTER  ABSORPTION 

been  shown  to  occur  under  ether,  and  sudden  cardiac  syncope  is  a 
very  rare  occurrence  under  it  and  has  not  been  investigated  except  by 
Henderson,  whose  views  have  been  given  already  (p.  205). 

A  second  form  of  accident  in  antesthesia  may  be  termed  that  from 
Overdosage  and  is  less  likely  to  be  fatal.  In  this  form  the  respiration 
becomes  shallower  and  finally  ceases  while  the  pulse  can  still  be  felt, 
or  the  heart  beat  can  still  be  felt  or  heard.  The  interval  between 
the  failure  of  the  breathing  and  that  of  the  pulse  varies  in  different 
accounts  and  in  some  both  are  said  to  have  disappeared  simultaneously. 
But  in  these  cases  the  gasping  respiration  is  not  seen,  which  is  character- 
istic of  the  cardiac  syncope.  This  accident  occurs  more  especially  when 
the  anaesthetic  has  been  pushed,  or  after  prolonged  inhalation.  It 
may  occur  under  chloroform  or  ether,  and  the  majority  of  fatalities 
under  the  latter  appear  to  be  of  this  character,  while  the  great  bulk 
of  chloroform  deaths  are  due  to  cardiac  syncope.  This  death  from 
overdosage  is  easily  elicited  in  animals  (Figs.  8  and  9),  and  has  been 
the  subject  of  a  large  amount  of  experimental  investigation,  which  has 
been  directed  chiefly  to  the  question  whether  the  respiration  or  the 
heart  is  the  first  to  fail.  This  appears  to  depend  on  the  concentration 
of  the  anjesthetic.  If  dilute  chloroform  or  ether  be  inhaled,  the  respira- 
tion always  ceases  several  minutes  before  the  heart,  which  continues  to 
beat  fairly  strongly  at  first  but  rapidly  becomes  weaker.  If  more 
concentrated  vapor  be  used,  the  respiration  again  ceases  before  the 
heart,  which  is,  however,  much  weakened  and  comes  to  a  standstill 
after  a  short  interval;  and  as  the  concentration  is  increased,  the  weak- 
ness of  the  heart,  at  the  moment  when  the  respiration  fails,  also 
increases,  and  the  interval  between  the  arrest  of  the  respiration  and 
that  of  the  heart-beat  becomes  shorter.  Finally,  when  air  saturated 
with  vapor  is  inhaled,  the  interval  l>etween  the  two  is  so  short  as  to  be 
inappreciable  (Fig.  12).  When  concentrated  vapor  of  either  chloro- 
form or  ether  is  inhaled,  the  pulse  may  be  so  weak  as  to  be  no  longer 
percei)tible  before  the  respiration  ceases,  and  the  anaesthetist,  therefore, 
believes  that  heart  failure  has  been  the  cause  of  death,  but  if  the  move- 
ments of  the  heart  be  registered  directly,  it  is  found  Ideating  as  long 
as  the  respiratory  movements  are  carried  on.  The  importance  of  the 
condition  of  the  heart  is  further  shown  by  the  results  of  attempts  to 
resuscitate  the  animal  after  the  respiration  has  ceased;  for  if  artificial 
respiration  be  commenced  at  once,  the  animal  can  invariably  be  restored 
to  life,  i)r()\ided  the  heart  has  not  been  weakened  too  nuich;  but  if 
concentrated  vapors  have  been  inhaled,  the  heart  is  unable  to  carry 
on  the  circulation,  and  the  animal  cannot  be  resuscitated. 

Hill  has  recently  pointed  out  that  the  failure  of  the  respiration  may 
be  caused  in  part  by  the  ana'mia  of  the  central  nervous  system  from 
the  fall  in  blood-pressure.  "^riie  weakness  of  the  heart  induced  by 
chlorofonn  is  tlicrcrorc  fraught  with  double  danger,  for  not  only  is  the 
cinnlnlioii  imperilled  by  it  but  the  res|)iration  is  indirectly  weakened. 

I'Vom  a  ])raetieal  point  of  \ie\v,  it  is  of  comparatively  little  im])or- 
tance  whether  there  are  a  few  lluttering  beats  of  the  heart  after  the 


ETHER  AND  CHLOROFORM  213 

last  inspiration  or  not.  The  all-imjiortant  question  is  wlietlier  tlie 
heart  has  been  so  injured  as  to  he  unahle  to  carry  on  the  circulation, 
and  this  is  decided  hy  the  concentration  of  the  vajjor  that  has  been 
inhaled.  Even  when  dihite  vapor  of  chloroform  is  inhaled,  the  heart 
is  considerably  injured  when  the  resj)iration  ceases,  while  under  ether, 
unless  very  concentrated  fumes  be  inhaled,  the  weakness  of  the  heart 
is  very  much  less. 

The  autopsy  in  cases  of  death  by  chloroform  or  ether  shows  no 
specific  lesions.  The  blood  is  often  dark  colored  from  the  asphyxia, 
and  the  heart  is  found  dilated.  Irritation  of  the  respiratory  passages 
may  be  present  in  ether  poisoning,  and  the  odor  of  the  anaesthetic  may 
be  recognized  in  the  different  organs.  Microscopic  examination  may 
show  some  alterations  in  the  cells  of  the  respiratory  centre  and  cardiac 
ganglia,  fragmentation  of  the  heart  muscle,  and  some  degeneration  of 
the  liver,  kidneys,  spleen  and  heart  after  chloroform  (Poroschin). 

Fig.  12 


D 


E 

Diagram  representing  the  state  of  the  heart  at  the  failure  of  respiration  from  an  anaes- 
thetic (chloroform  or  ether).  A  represents  the  respiratory  movements,  which  cease  very 
early  in  the  tracing,  B,  the  pulsations  of  the  heart  at  this  point  if  the  anajsthetic  vapor 
has  been  much  diluted  with  air,  C  if  it  is  of  medium  strength,  D  if  very  concentrated,  and 
E  if  saturated.     The  heart  pulsations  are  recorded  by  the  mercury  manometer. 

Of  late  years  a  good  deal  of  interest  has  been  excited  by  the  dis- 
covery that  the  perils  of  anaesthesia  are  not  over  when  consciousness 
returns,  but  that  fatal  consequences  may  follow  several  days  later. 
These  late  fatalities  are  due  to  fatty  changes  of  the  heart,  liver  and 
kidneys  or  to  diabetic  coma  in  the  case  of  chloroform,  to  bronchitis, 
pulmonary  oedema  and  pneumonia  after  ether.  No  reliable  data  are 
as  yet  available  as  to  the  frequency  of  these  sequelae,  as  it  is  very 
difficult  to  distinguish  between  the  results  of  the  aiuesthetic  and  the 
ordinary  forms  of  disease.  Even  the  proportion  of  cases  in  which 
albuminuria  occurs  after  chloroform  seems  to  vary  remarkably  in 
different  hospitals,  for  it  is  given  as  low  as  5  per  cent,  by  some  authors 
and  as  high  as  30  per  cent,  by  others;  this  may  perhaps  be  exjihuned 
by  differences  in  the  duration  of  the  anaesthesia.     The  irritant  effects 


214       SUBSTANCES  ACTING  AFTER  ABSORPTION 

of  ether  and  the  liabiHty  to  pulmonary  affections  afterward  have  been 
so  evident  that  some  surgeons  have  returned  to  the  use  of  (•hk)roform, 
believing  that  the  late  effects  in  ether  claimed  as  high  a  proportion  of 
victims  as  the  more  immediate  eflFects  of  chloroform.  'J'his  irritant 
action  of  ether  may  be  avoided  to  some  extent  by  allowing  the  vapor 
to  be  inhaled  in  a  more  dilute  form  than  is  often  used  in  inducing 
anaesthesia.  And  there  is  reason  to  believe  that  the  pulmonary  effects 
are  often  intensified  by  the  air  inhaled  being  chilled  by  the  evaporation 
of  the  ether,  and  that  they  may  be  lessened  if  this  is  avoided  by  suitable 
inhalers. 

Apparatus  and  Principles. — The  principles  on  which  the  safe  pro- 
duction of  anaesthesia  is  based,  then,  are  comparatively  simple,  but 
their  interpretation  into  practice  has  given  rise  to  various  methods. 
A  large  number  of  inhalers  have  been  introduced  with  the  object  of 
permitting  of  only  a  certain  degree  of  concentration  of  the  vapors. 
But  the  great  majority  of  these  are  entirely  erroneous  in  principle; 
the  concentration  of  the  vapor  being  determined  by  the  character 
of  the  respiration  of  the  patient,  and  the  number  of  accidents  has  not 
been  appreciably  reduced  by  their  use.  In  one  of  these  the  amount 
of  oxygen  available  for  respiratjon  was  found  to  be  reduced  to  5  per 
cent.,  while  the  carbonic  acid  had  risen  to  7.8  per  cent,  after  two  min- 
utes' respiration.  This  mixture  of  gases  is  insufficient  to  support  the 
combustion  of  a  candle,  and  is  very  near  that  which  is  immediately 
fatal  to  animal  life.  In  another  the  concentration  of  the  vapor  was 
found  to  vary  between  1.2  and  10.4  volumes  per  cent.  Several  appa- 
ratus have  recently  been  constructed  on  correct  principles,  which 
allow  of  an  exact  gradation  in  the  strength  of  the  vapor  inhaled,  but 
they  are  exceedingly  cumbrous,  and  while  they  might  be  used  in  hos- 
pitals, are  certainly  not  available  for  ordinary  practice. 

The  advantage  of  this  principle  of  measuring  the  concentration  of  the 
vapors  is  further  only  relative,  for  it  has  been  shown  that  vapors  so  dilute 
as  to  be  absolutely  safe  do  not  induce  an.Tsthesia  within  a  reasonable 
time.  Thus  1  per  cent,  chloroform  seems  to  be  practically  safe,  but 
no  surgeon  will  wait  ^-f  hr.  for  the  aniesthetist.  To  induce  an<\?sthesia, 
therefore,  vapors  have  to  be  used  which  would  in  time  be  fatal,  and 
only  after  the  reflexes  disappear  is  it  possible  to  reduce  the  concentration 
to  the  point  of  absolute  safety.  The  responsibility  of  the  anaesthetist 
is,  therefore,  lessened,  but  by  no  means  entirely  removed  by  these 
methods.  In  the  vast  majority  of  cases,  however,  much  simpler 
apparatus  is  used,  and  the  ordinary  mask  or  towel  on  which  the  anaes- 
thetic is  poured  is  not  responsible  for  a  larger  proportion  of  accidents 
than  the  more  complicated  forms  of  ap]mratus.  When  no  inhaler  is 
used,  the  aniesthetist  attempts  to  regulate  the  concentration  of  the 
vapor  according  to  the  symptoms,  and  this  can  be  done  with  com])lete 
success  by  watching  the  respiration  closely.  If  the  breathing  be  shallow, 
much  less  concentrated  vapor  is  inhaled  into  the  alveoli  than  if  it  be 
deep  and  gasping,  for  in  ordinary  resi)irati()n  the  air  in  the  smaller 
bronchioles  and  alveoli  is  not  exchanged  directly  with  every  respiration, 


ETHER  AND  CHLOROFORM  215 

but  only  by-  a  process  of  diffusion  from  the  larger  air  passages.  The 
deeper  the  respiration,  however,  the  further  does  the  vapor  penetrate 
and  the  lower  the  concentration  needed  to  change  the  quantity  in  the 
blood.  An  experienced  anaesthetist,  by  watching  the  respiration,  raising 
the  mask  during  deep  breathing  and  replacing  it  when  it  becomes 
steady,  can  regulate  with  sufficient  nicety  the  concentration  of  the 
anaesthetic  in  the  alveoli  and  thereby  the  quantity  in  the  blood.  When 
anaesthesia  has  been  attained,  he  of  course  reduces  the  concentration 
until  the  return  of  the  reflexes  indicates  awakening  consciousness,  and 
even  then  applies  much  smaller  quantities  than  were  necessary  at  first. 

This  method  of  inducing  anaesthesia  requires  the  antesthetist  to  watch 
only  the  respiration  and  the  reflexes,  and  is  that  advised  by  Simpson 
and  his  followers  (see  Hyderabad  Commission  Report).  A  further 
safeguard  has  been  sought  for  in  the  condition  of  the  pulse,  and  this 
would  seem  the  natural  consequence  of  what  has  been  stated  above  as  to 
the  importance  of  the  condition  of  the  heart.  The  pulse,  however,  is 
not  very  reliable  as  a  guide  in  ana?sthesia,  for  in  the  second  stage,  in 
which  a  certain  number  of  fatalities  occur,  it  is  quickened  by  the  excite- 
ment and  may  be  irregular,  and  only  gives  indications  of  danger  when 
it  is  too  late  to  take  measures  to  prevent  it.  In  the  third  stage  it  may 
become  gradually  weaker,  and  thus  indicate  approaching  danger,  but 
if  the  respiration  be  watched  the  warning  is  given  earlier.  A  large 
number  of  anaesthetists  advise,  however,  the  pulse  and  respiration  both 
be  watched,  and  this  would  seem  to  be  the  safest  method,  provided 
always  that  the  anaesthetist  does  not  depend  on  the  pulse  too  much  for 
indications  of  danger,  and  does  not  allow  it  to  distract  his  attention 
from  the  more  important  indications  given  by  the  respiration. 

Preliminary  Examination. — Before  anaesthesia,  a  careful  examination 
should  be  made  of  the  condition  of  the  patient,  and  if  there  is  great 
anxiety  and  excitement,  a  hypodermic  injection  of  morphine  may  be 
given  beforehand,  or  chloral  may  be  prescribed,  but  these  are  rarely 
necessary.  Valvular  disease  of  the  heart  does  not  contra-indicate  an 
anesthetic  unless  there  are  marked  symptoms  of  inefficiency,  such  as 
dropsy  or  oedema.  In  fatty  disease  of  the  heart,  on  the  other  hand, 
chloroform  is  to  be  avoided,  and  if  it  seems  extensive,  ether  is  also 
dangerous  from  the  strain  put  on  the  circulation  during  the  excite- 
ment. Chloroform  is  liable  to  induce  fatty  degeneration  of  the  heart, 
and  for  this  reason  it  would  not  seem  advisable  to  use  it  in  successive 
operations  on  the  same  patient.  Atheromatous  arteries  are  dangerous 
from  the  tendency  to  apoplexy  during  the  second  stage  also,  and  if 
anaesthesia  is  absolutely  necessary,  an  opiate  ought  to  be  given  pre- 
viously. Anaesthesia  is  said  to  be  dangerous  in  cases  of  brain  tumor, 
and  this  may  possibly  arise  from  the  fragility  of  the  vessels.  In  cases 
of  bronchitis  and  catarrh  of  the  air  passages,  chloroform  is  to  be  pre- 
ferred to  ether  as  it  is  less  irritating,  while  in  Bright's  disease  chloro- 
form is  generally  more  injurious  than  ether  from  the  resultant  albu- 
minuria and  tendency  to  fatty  degeneration,  although  ether  is  also 
believed  by  many  to  disturb  the  renal  functions.    Advanced  diabetes 


21G  SUBSTANCES  ACTING  AFTER  ABSORPTION 

coiitni-indicatcs  aniestliesia,  tlie  siifi;ar  increasing;  in  the  urine  after- 
wards and  coma  and  death  sometimes  sujx'rvening  in  the  course  of  a 
few  days.  Da  Costa  recommends  that  where  there  are  symptoms  of 
ajittmia,  an  examination  of  the  blood  should  be  made  before  anaes- 
thesia, and  states  that  where  the  haemoglobin  is  found  to  be  deficient, 
great  care  is  necessary  and  that  where  it  is  lower  than  50  per  cent,  of 
the  normal,  an  anaesthetic  is  contra-indicated. 

Practical  Anaesthesia. — The  patient  should  have  a  light,  easily  di- 
gested meal  2-4  hours  before,  so  that  the  stomach  may  be  empty  and 
vomiting  avoided  as  far  as  possible.  The  bowels  should  also  be  regu- 
lated the  day  before  for  the  same  reason.  He  should  then  l)e  laid  on 
a  table  of  suitable  height  with  a  low  pillow,  and  should  remove  false 
teeth  and  any  other  foreign  object  from  the  mouth.  The  clothing 
about  the  neck,  chest  and  abdomen  is  to  be  loosened  or  removed  to 
allow  of  perfectly  free  respiration,  but  warm  blankets  or  warm  bottles 
should  be  applied  as  far  as  possible  to  prevent  the  fall  of  temperature 
if  the  operation  is  likely  to  be  a  long  one.  The  eyes  are  closed  in  order 
to  protect  the  conjunctiva  from  the  irritating  vapor.  The  anaesthetic 
is  then  applied  on  a  towel  or  on  a  mask,  which  ought  to  be  freely  per- 
meable by  the  air,  and  ought  not  to  fit  closely  to  the  face.  Masks  were 
formerly  employed  to  administer  ether  (closed  method)  in  which  the 
respiration  was  seriously  impeded,  so  that  the  patient  was  partially 
asphyxiated  besides  receiving  a  highly  concentrated  ether  vapor.  It 
must  be  remembered  that  the  air  passes  through  cloth  with  much 
greater  difficulty  when  it  is  wet  by  the  saliva  and  mucus,  antl  that  a 
mask  which  is  freely  permeable  at  the  commencement  of  an  operation, 
may  lead  to  asphyxia  after  it  has  been  soaked  during  the  first  and 
secoufl  stages.  The  patient  is  instructed  to  breathe  as  regularly  as 
possible,  or  to  count  from  one  upwards,  and  some  of  the  anaesthetic  is 
(Iropi)ed  on  the  mask.  If  the  breath  be  held,  the  mask  should  be 
raised  a  little  from  the  face,  as  the  next  inspiration  will  be  a  very  deep 
one.  During  the  excitement  stage  the  respiration  is  irregular,  and 
great  care  must  be  taken  to  avoid  the  inhalation  of  too  concentrated 
vai)or.  As  soon  as  the  conjunctival  reHex  disappears,  the  mask  is 
raised,  and  is  replaced  only  when  it  reappears  or  when  the  patient 
evinces  signs  of  pain.  The  object  of  the  anaesthetist  should  be  to  main- 
tain an  even  anjesthesia  and  to  avoid  sudden  changes;  this  is  best 
attained  by  raising  and  lowering  the  mask  slightly,  or  by  varying  the 
number  of  droj)s  of  anaesthetic  falling  on  it;  the  inhalation  should  not 
\}v  completely  interrupted  except  in  danger.  Throughout  the  anaesthesia 
care  must  be  taken  to  ])revent  any  interference  with  the  respiration 
by  the  operator  leaning  on  the  thorax  or  abdomen.  Very  often  ster- 
torous respiration  sets  in  from  the  tongue  falling  back  into  the  throat, 
and  this  has  to  be  remedied  by  ])ressing  forward  the  angle  of  the  jaw, 
or  if  this  is  not  sufficient,  by  i)ulling  out  the  tongue  with  a  blunt-pointed 
forceps.  \'omitiiig  is  a  very  common  occurrence  in  aiia'sthesia,  and  when 
it  sets  in,  the  head  is  tnrn(vl  to  one  side  ami  the  \ oiiiitccl  matter  renio\'ed 
with  a  sponge. 


ETHER  AND  CHLOROFORM  217 

A  more  serious  accident  is  the  failure  of  the  respiration.  A  reflex 
arrest  often  occurs  in  the  first  stage,  but  is  not  of  importance  in  itself, 
but  only  from  the  deep  gasping  iiisi)iration  wliicli  follows  it.  If  tiie 
anaesthetic  be  given  too  long  in  concentrated  form,  however,  the  respi- 
ration fails  from  direct  action  on  the  centre,  and  this  demands  imme- 
diate attention.  The  head  ought  to  be  lowered  at  once,  and  the  lower 
limbs  elevated,  in  order  to  drive  the  blood  to  the  head  as  far  as  pos- 
sible and  thus  remedy  the  anaemia  of  the  brain  from  the  weakness  of 
the  heart  that  accompanies  the  cessation  of  the  respiration.  The 
epiglottis  must  be  raised  by  pressing  forward  the  angles  of  the  jaw 
(Hare),  or  by  dragging  forward  the  base  of  the  tongue  with  hook  or 
finger.  Artificial  respiration  in  one  or  other  form  ought  to  be  commenced 
at  once,  and  carried  on  as  long  as  is  necessary;  a  large  number  of  methods 
of  performing  artificial  respiration  have  been  proposed,  but  they  can 
only  be  taught  in  a  practical  class  and  need  not  be  entered  upon  here.^ 
If  the  pulse  is  weak,  intermittent  pressure  over  the  heart  may  aid  it  in 
carrying  on  the  circulation,  and  in  some  cases  the  abdominal  cavity 
has  been  rapidly  opened  and  the  heart  compressed  between  one  hand 
below  the  diaphragm  and  the  other  on  the  chest  wall.  This  heroic 
measure  has  in  some  cases  restored  the  heart  beat  and  the  respiration. 
Various  drugs  have  been  recommended  in  these  cases,  but  it  is  exceed- 
ingly^ questionable  whether  they  are  really  of  service;  alcohol,  ammonia 
and  ether  have  been  injected  subcutaneously,  and  may  conceivably 
cause  such  local  irritation  as  to  reinstate  the  respiration  reflexly,  although 
this  is  improbable.  Strychnine,  caffeine  and  atropine  have  been 
injected  as  respiratory  stimulants,  and  digitalis  to  strengthen  the  heart 
contraction;  as  a  matter  of  fact,  how^ever,  if  the  circulation  is  strong 
enough  to  cause  the  absorption  of  these  drugs  and  carry  them  to  the 
respiratory  centre  and  the  heart,  the  patient  will  recover  wdth  the 
artificial  respiration  alone,  while  on  the  other  hand,  they  are  of  no 
value  unless  absorbed.  Nitrite  of  amyl  is  useless,  as  it  can  only  affect 
the  heart  by  reducing  the  blood-pressure,  wdiich  is  already  dangerously 
low.  In  animal  experiments,  the  best  results  are  obtained  by  the 
intravenous  or  intracardiac  injection  of  adrenaline  in  saline  solution. 

Cardiac  syncope  and  fibrillation  is  the  most  dangerous  accident  of 
anaesthesia,  and  probably  is  irremediable  when  fully  developed.  The 
treatment  consists  in  inversion,  artificial  respiration,  and  massage  of  the 
heart.  Embley  recommends  the  injection  of  atropine,  on  the  view  that 
the  condition  is  due  to  inhibition,  and  it  might  be  thrown  into  the 
heart  directly  by  means  of  a  long  hypodermic  needle.  The  experiments 
of  Levy  show  that  adrenaline  favors  ventricular  fibrillation  under  chloro- 
form, and  this  powerful  stimulant  is  therefore  inadmissible  in  syncope. 

In  the  course  of  very  long  operations  it  is  recommended  to  allow 
the  patient  to  almost  recover  consciousness  at  intervals,  but  this  is 
deprecated  by  Henderson  and  Levy  as  favoring  the  onset  of  syncope. 
It  must  be  remembered  that  in  prolonged  anaesthesia  comparatively 

1  For  a  comparison  of  the  efficacy  of  different  forms  see  Schafer,  Medico-Chinirgical 
Transactions,  vol.  Ixxxvi,  supplement,  1904. 


218  SUBSTANCES  ACTING  AFTER  ABSORPTION 

small  quantities  are  required  to  maintain  unconsciousness  when  it  is 
once  comj)letely  reached,  and  at  the  same  time  that,  owing  to  the  fall 
of  temperature,  and  the  prolonged  action  of  the  drug,  the  quantity 
necessary  to  j^roduce  cessation  of  the  respiration  and  the  heart  is  much 
smaller  than  during  shorter  operations.  In  order  to  induce  anaes- 
thesia within  a  reasonable  time,  comparatively  strong  vapor  may  be 
used,  but  as  soon  as  unconsciousness  is  reached,  the  vapor  ought  to  be 
diluted  as  far  as  is  compatible  with  the  continuation  of  the  narcosis.' 

On  the  completion  of  the  operation,  the  patient  seldom  requires 
further  attention  from  the  antesthetist;  after  prolonged  anaesthesia 
heat  may  be  applied  by  warm  bottles,  etc.,  as  the  temperature  often 
continues  to  fall  for  some  time  after  the  administration  of  the  drug 
has  ceased.  If  vomiting  persists  after  the  recovery  of  consciousness, 
ice  may  be  sucked,  or  bismuth  may  be  prescribed.  The  inhalation 
of  vinegar  has  been  recommended  and  relief  is  sometimes  given  by 
lavage  of  the  stomach. 

The  patient  should  always  be  placed  in  the  recumbent  position 
when  possible,  as  otherwise  the  weakened  heart  tends  to  drive  the 
blood  in  the  direction  of  least  resistance,  that  is,  downward,'  and  in 
the  depressed  condition  of  the  vasomotor  centre,  this  is  not  counter- 
acted by  the  contraction  of  the  arterioles  of  the  abdomen,  and  antemia 
of  the  brain  and  fainting  are  liable  to  result.  The  operation  ought 
not  to  be  commenced  until  anaesthesia  is  complete;  otherwise  reflex 
inhibition  of  the  heart  or  syncope  may  result  and  lead  to  fatal  results. 

Various  drugs  have  been  advised  as  preliminaries  to  anaesthesia, 
generally  with  the  object  of  preventing  the  reflex  arrest  of  the  respira- 
tion and  heart.  Thus  atropine  has  been  proposed  to  paralyze  the 
vagus,  and  to  arrest  the  mucous  secretion  and  vomiting,  and  spraying 
of  the  nose  with  cocaine  has  recently  been  advised  to  paralyze  the 
sensory  terminations  and  so  prevent  the  irritation  which  sets  up  the 
reflexes.  It  has  been  proposed  to  dilute  ether  or  chloroform  vapor 
with  oxygen  instead  of  air,  but  this  has  no  advantages.  In  order  to 
avoid  the  unpleasant  suffocating  effects  of  ether  and  to  permit  of  less 
concentrated  vapor  being  used,  the  injection  of  0.01  G.  (-g  gr.)  of  mor- 
phine along  with  0.5  mg.  (y.jo  gr.)  of  hyoscine  has  been  advocated  as  a 
preliminary  to  ether  anaesthesia,  and  this  has  become  a  routine  pro- 
cedure in  some  clinics  from  which  satisfactory  results  are  recorded.  In 
others,  some  less  unpleasant  aniesthetic,  such  as  nitrous  oxide  or  ethyl 
chloride,  is  used  to  induce  anaesthesia,  which  is  afterward  maintained 
by  ether. 

Intravenous  Infusion  Anaesthesia. — The  intravenous  injection  of  ether 
has  been  advocated  recently  (Hurkhardt),  with  the  object  of  avoiding 
the  local  irritant  efl'ccts  of  ether  vapor  in  the  lungs,  and  has  proved 

'  In  anicsthesia  with  measured  percentages  of  chloroform,  Alcock  found  it  best  to 
commence  with  vapor  lA  1  jjcr  cent.,  rising  to  2  per  cent,  after  two  minutes  and  to  25-8 
per  cent,  in  five  minutes;  this  strength  was  continued  until  ana'sthesia  was  attained,  after 
which  tlie  concentration  was  re(hice(i  to  2  per  cent,  and  further  to  1  per  cent,  in  the  course 
of  twenty  miiuites. 


ETHER  AND  CHLOROFORM  219 

useful,  especially  in  operations  on  the  mouth  and  throat,  in  whicli  the 
anaesthetist  is  liable  to  he  hampered  by  the  surgeon.  A  solution  of 
5-8  per  cent,  of  ether  in  sterilized  Kinger's  solution  is  slowly  infused 
through  a  cannula  introduced  into  a  vein,  and  as  anaesthesia  is  induced 
the  rate  of  flow  is  lessened  until  the  point  is  reached  which  is  just  suffi- 
cient to  maintain  unconsciousness.  An  injection  of  atropine  is  often 
given  previously  to  lessen  the  mucous  secretion  of  the  bronchi,  and 
morphine  and  hyoscine  are  also  injected  previously  by  some  anties- 
thetists.  The  method  has  advantages  in  some  conditions  but  is  liable 
to  cause  hsemoglobinuria  and  is  not  adapted  for  ordinary  surgical  work, 
in  which  the  inhalation  method  is  simpler  and  involves  less  apparatus. 
Vomiting  and  marked  mucous  secretion  occur  from  intravenous  antes- 
thesia,  the  latter  perhaps  from  the  ether  excretion  through  the  lungs, 
which  proceeds  rapidly.  Soporifics,  such  as  hedonal,  have  been  sub- 
stituted for  ether  for  infusion,  but  induce  a  very  prolonged  anaesthesia, 
which  in  some  cases  has  proved  fatal. 

Various  Mixtures  of  the  Anaesthetics  have  been  advised  at  different  times. 
Of  these  the  ACE  mixture  (alcohol  1,  ether  2,  and  chloroform  3  parts  by  vol- 
ume) is  the  best  known.  Its  use  has,  however,  been  attended  with  numerous 
fatalities,  as  was  only  to  be  expected  from  a  consideration  of  the  volatility  of 
the  different  ingredients.  Ether,  being  the  most  volatile,  is  first  inhaled,  and 
then  chloroform,  and  last  of  all  the  alcohol.  The  safe  concentration  of  ether 
is,  however,  much  greater  than  that  of  chloroform,  and  a  vapor  which  may 
be  perfectly  safe  as  long  as  it  consists  of  ether  for  the  most  part,  may  become 
exceedingly  dangerous  when  it  consists  of  chloroform.  This  method,  therefore, 
increases  the  responsibiUty  of  the  ansesthetist  by  leaving  hip  in  complete 
ignorance  as  to  the  composition  of  the  anaesthetic  at  any  given  time.  The  same 
criticism  applies  to  a  mixture  of  anaesthetics  advocated  by  Schleich  and  con- 
taining ether,  chloroform  and  petrol,  wliich  enjoyed  a  brief  popularity  some 
years  ago. 

The  action  of  such  mixtures  is  a  simple  sum  of  the  actions  of  the  constituents; 
the  presence  of  chloroform  does  not  intensify  the  anaesthetic  action  of  ether, 
except  in  so  far  as  the  chloroform  itself  anaesthetizes.  In  other  words  there  is 
no  synergism  between  chloroform  and  ether  such  as  has  been  shown  to  exist 
between  morphine  and  hyoscine  for  example. 

Ethyl  Chloride  (CaHsCl)  has  been  advocated  of  recent  years  as  an  anaesthetic 
for  minor  operations  and  examinations,  and  possesses  the  advantages  of  acting 
very  quickly  and  of  leaving  no  after  effects  except  occasionally  some  nausea, 
the  patient"  generally  feeling  perfectly  well  in  a  few  minutes.  It  is  kept  in 
sealed  tubes  and  inhaled  through  a  mask  as  it  is  extremely  volatile,  boiling 
at  about  12°  C.  Anesthesia  is  obtained  in  about  two  to  five  minutes,  but 
complete  muscular  relaxation  is  often  absent.  Recovery  follows  a  few  min- 
utes after  the  removal  of  the  mask.  It  is  not  unpleasant  to  inhale  and  gen- 
erally induces  no  excitement  or  other  unfavorable  symptoms.  The  pulse 
is  generally  slowed,  while  the  respiration  is  deep.  Embley  states  that  in  ani- 
mals the  effects  are  similar  to  those  of  chloroform,  but  that  it  is  less  poisonous 
to  the  heart,  about  nineteen  times  as  concentrated  vapor  being  necessary  to 
weaken  it.  The  concentration  of  ethyl  chloride  vapor  necessary  to  induce  car- 
diac inhibition  is  four  times  that  of  chloroform,  and  this  inhibition  is  not  fatal 
as  the  heart  muscle  is  less  affected.  The  vapor  may  be  inhaled  in  5-7  per 
cent,  concentration  without  inducing  inhibition  in  the  dog.  Nicloux  found 
about  20  mgs.  of  ethyl  chloride  per  100  c.c.  in  the  blood  in  light  ana-sthesia 
from  30  to  150  mgs.  in  deep  anaesthesia  and  40-180  at  death.  A  number  of 
fatalities  have  occurred  under  its  use,  about  one  in  three  thousand  of  those 


220  SUBSTANCES  ACTING  AFTER  ABSORPTION 

anjcsthetized.  Some  major  operations  have  been  performed  under  ethjd  chloride, 
hut  it  is  found  difficult  to  maintain  a  uniform  anesthesia,  owing  to  the  rapiditj' 
witli  which  consciousness  returns.  It  is  often  emplo.yed  to  introduce  anaesthesia, 
which  is  then  maintained  with  ether.  Elth}'!  chloride  should  not  be  administerctl 
in  larger  quantities  than  4-5  c.c. 

Various  other  members  of  the  fatty  series  have  been  introduced  as  general 
ana?sthetics  at  different  times,  but  few  of  them  have  proved  to  have  any  advan- 
tage over  chloroform  and  ether,  and  fatalities  have  occurred  after  all  of  those 
that  have  received  a  wide  trial.  Pental,  trunethylethylene  ((CH3)2  C  =  CHCHs) 
was  introduced  for  short  operations  but  a  number  of  accidents  occurring 
under  it  have  curtailed  its  use.  It  produces  ansesthesia  before  the  reflexes 
disappear  or  the  nmscles  relax,  and  not  infrequently  the  jaws  are  tightly  closed 
after  consciousness  is  lost.  In  some  cases  tremor  and  convulsive  attacks  have 
occurred  during  its  administration,  Ijut  it  seems  to  have  very  little  action 
on  the  heart  or  circulation.  Ethyl  Bromide  (C2H6Br)  has  also  been  used  for 
short  operations  instead  of  cliloroform,  and  produces  anaesthesia  with  great 
rapidity.  Consciousness  returns  quickly  after  the  removal  of  the  mask,  but 
the  inhalation  is  not  so  pleasant  as  that  of  ethyl  chloride  and  patients  com- 
plain of  greater  depression  and  discomfort  afterward.  Hennicke  found  that 
10  vol.  per  cent,  of  ethyl  bromide  w^ere  necessary  to  anaesthetize  animals  within 
five  minutes,  and  that  if  this  concentration  were  maintained,  death  occurred  in 
fifteen  minutes,  so  that  it  is  by  no  means  to  be  considered  a  perfectly  safe 
anaesthetic;  several  deaths  have  occurred  from  its  use  in  dentistry.  Both 
pental  and  ethyl  bromide  are  administered  on  a  mask  in  the  same  w^ay  as  ether. 
Ethjd  bromide  must  be  distinguished  from  ethylene  bromide  (C2H4Br2)  which 
is  a  much  more  dangerous  anaesthetic.  Ethyl  bromide  is  verj'  liable  to  decom- 
position when  kept  long,  and  is  often  furnished  in  an  impure  form;  it  ought 
to  be  perfectly  colorless,  as  a  yellowdsh  color  indicates  decomposition,  often 
with  the  presence  of  free  bromine. 

The  other  members  of  this  series  possess  no  practical  importance.  It  may 
be  mentioned  that  tetrachloride  of  carbon  (CCU)  differs  from  the  others  in 
causing  conv-ulsions,  while  perchlorethane  (CiCle)  is  a  crj-staUine  sohd  and 
possesses  too  high  a  boiling  point  to  be  available  for  inhalation. 

Therapeutic  Uses. — Anaesthesia  is  generally  induced  for  the  purpose 
of  surgical  operations  and  examinations,  and  in  labor.  Until  recent 
years,  when  it  was  necessary  to  perform  an  operation  or  manipulation 
involving  much  pain,  the  surgeon  had  to  consider  only  which  of  the 
two  general  anaesthetics  was  the  better  adapted  to  the  case.  But  the 
improvements  introduced  in  the  methods  of  inducing  local  anaesthesia 
and  the  reintroduction  of  nitrous  oxide  and  ethyl  chloride  as  surgical 
antesthetics  have  now  enlarged  his  field  of  choice,  and  the  further 
question  has  to  be  met  whether  unconsciousness  is  desirable,  or  whether 
the  necessities  of  the  case  may  not  be  met  by  paralyzing  sensation  at 
the  seat  of  operation  only.  The  advantages  claimed  for  local  anaes- 
thesia will  be  discussed  under  cocaine,  but  the  general  conditions  in 
which  chloroform  and  ether  are  to  be  i)refcrre(l  may  be  stated  shortly 
(see  also  nitrous  oxide).  General  anaesthesia  is  absolutely  essential 
where  complete  relaxation  of  the  muscles  is  desired,  and  w^here  the 
movements  of  the  patient  may  imperil  the  success  of  the  operation. 
Operations  on  the  abdominal  organs  and  around  joints  and  such  others 
as  iii\'olvc  wide  and  deep  incisions  will  almost  certainly  continue  to  be 
performed  under  chloroform  or  ether,  although  a  few  such  operations 
have  been  performed  under  cocaine.     In  many  less  serious  operations 


ETHER  AM)  CHLOROFORM  221 

it  is  necessary  also  to  have  recourse  to  the  older  methods,  which  allow 
greater  freedom  to  the  surgeon,  who  is  under  no  apprehension  that 
he  may  reach  a  sensitive  area  and  has  thus  one  less  source  of  anxiety 
than  if  the  anjesthesia  were  localized.  Another  argument  for  the  use 
of  general  ans^sthetics  is  the  effect  which  the  anxiety  and  the  sights 
and  sounds  of  the  operating  room  may  have  on  a  nervous  patient  even 
when  no  actual  pain  is  felt.  And  a  considerable  amount  of  practice 
is  required  before  complete  local  anaesthesia  can  be  induced  over  an 
extensive  field  of  operation,  while  the  surgeon  has  often  to  interrupt 
his  manipulations  in  order  to  admit  of  a  fresh  area  being  rendered 
analgesic.  But  there  is  no  question  that  many  operations  in  which 
ether  or  chloroform  have  hitherto  been  employed,  will  in  the  future  be 
performed  more  often  under  local  anaesthesia  or  nitrous  oxide.  In 
this  class  may  be  included  most  minor  operations  in  which  only  very 
short  or  partial  anaesthesia  is  necessary  and  in  which  no  complications 
are  to  be  anticipated.  Nitrous  oxide  and  ethyl  chloride  are  scarcely 
to  be  regarded  as  rivals  to  ether  and  chloroform  in  any  but  minor 
operations.  But  in  these  they  have  the  great  advantage  that  the 
patient  can  be  dismissed  within  a  few  minutes  after  the  operation  is 
completed,  while  if  ether  or  chloroform  is  employed  complete  recovery 
is  only  reached  after  several  hours;  when  the  latter  are  used  in  minor 
operations,  the  discomfort  resulting  from  the  anaesthetic  may  be  alto- 
gether out  of  proportion  to  the  actual  surgical  manipulation. 

During  labor  only  the  lighter  degrees  of  anaesthesia  are  necessary, 
the  object  being  to  dull  the  pain  without  lessening  to  any  marked 
extent  the  reflex  irritability  of  the  spinal  cord,  and  accidents  are 
extremely  rare  in  this  use  of  anaesthetics,  although  the  common  state- 
ment that  they  are  unknown  is  incorrect.  Some  cases  have  been 
recorded  in  which  it  is  believed  that  chloroform  was  fatal  to  the  child 
and  not  to  the  mother,  but  it  is,  of  course,  impossible  to  state  with 
certainty  that  the  anaesthetic  was  the  cause  of  death.  If  too  deep 
anaesthesia  is  produced,  however,  it  is  quite  conceivable  that  the  labor 
may  be  prolonged,  or  the  blood-pressure  so  reduced  as  to  lead  to  an 
imperfect  exchange  of  gases  in  the  placenta  and  thus  to  the  death  of 
the  infant;  or,  as  another  explanation  it  might  be  suggested  that  the 
irritability  of  the  respiratory  centre  of  the  child  may  be  so  reduced 
that  it  fails  to  react  when  the  placental  circulation  is  interrupted. 

Anaesthetics  are  also  employed  in  cases  of  extreme  irritability  of 
the  central  nervous  system,  as  in  strychnine  poisoning,  tetanus  or  other 
convulsive  affections.  In  order  to  reduce  these,  it  is  unnecessary  to 
produce  deep  anaesthesia,  a  few  whiffs  of  chloroform  being  generally  suf- 
ficient to  produce  quiet,  often  without  affecting  the  consciousness  to  any 
marked  extent.  In  cases  of  very  acute  pain,  chloroform  or  ether  may  be 
used,  but  as  a  general  rule  morphine  or  opium  is  preferable,  as  the  action 
lasts  much  longer  and  the  administration  is  much  more  convenient. 

The  local  action  of  chloroform  and  ether  on  the  stomach  and  skin 
is  entirely  independent  of  their  action  as  amesthetics,  and  has  been 
discussed  separately  (see  page  69). 


222  SUBSTANCES  ACTING  AFTER  ABSORPTION 

Preparations. 

U.  S.  P. — Chloroformum,  a  liquid  containing  99-99.4  per  cent,  by  weight 
of  absolute  chloroform  (CHCI3)  and  0.6-1  per  cent,  of  alcohol. 

.-Ether,  ether,  a  hquid  composed  of  about  96  per  cent,  by  weight  of  absolute 
ether  or  ethyl  oxide  ((C2H5)20)  and  about  4  per  cent,  of  alcohol  containing  a 
little  water. 

iExHYLis  Chloridum,  ethyl  chloride  (C2H5CI),  an  extremely  volatile  Uquid 
boiling  at  12.5-13°  C.  (about  55°  F.). 

B.  P— Chloroformum,  contains  98  per  cent,  of  chloroform  (CHCI3),  and  2 
per  cent,  of  absolute  alcohol.     Its  specific  gravity  is  1.483-1.487. 

J^^THER  PuRiFiCATUs,  ether,  contains  about  95  per  cent,  of  absolute  ether 
((C2H6)20)  along  with  some  alcohol  and  water  and  has  a  specific  gravity  of  0.720. 

Ethyl  Chloridum,  C2H5CI,  a  very  volatile  liquid  of  specific  gravity  0.92-0.96, 
and  containing  not  less  than  99.5  per  cent,  of  ethyl  chloride. 

Chloroform  is  ordinarily  formed  by  the  action  of  chlorine  on  alcohol,  the 
chlorine  being  added  in  the  form  of  chlorinated  lime.  The  crude  drug  is 
purified  by  repeated  washing  with  water  and  sulphuric  acid,  and  dried  over 
calcium  chloride.  The  fatahties  following  its  use  have  frequently  been  ascribed 
to  impurities,  and  a  certain  demand  has  arisen  for  a  purer  article  than  that 
required  by  the  pharmacopoeias.  Another  method  of  preparation  has  therefore 
been  introduced,  the  decomposition  of  chloral  bj^  soda  {Chloroformum  e  Chloral 
prceparatum) .  Other  pure  forms  are  prepared  from  ordinary'  chloroform  by 
crystalhzing  it  by  cold  (Pictet),  or  by  forming  a  compound  with  salicylid  and 
decomposing  it  again  by  sUght  heat.  Chloroform  (Aiischutz)  or  Chloroform 
{Salicylid) . 

The  impurities  of  cliloroform  are  due  partly  to  imperfect  manufacture  and 
partly  to  decomposition.  Along  with  the  chloroform  there  distils  over  a 
small  quantity  of  heavy,  oily  fluid,  which  may  be  isolated  bj'  Pictct's  method, 
but  whose  composition  is  entireh'  unknown.  DuBois-Reymond  found  that 
this  fluid  acted  more  strongly  on  the  heart  than  pure  chloroform,  but  it  is 
very  questionable  whether  the  minute  quantities  inhaled  in  ordinary  anaes- 
thesia produce  effects  of  anj'  importance,  and,  on  the  other  hand,  it  is  quite 
certain  that  the  use  of  absolutely  pure  chloroform  does  not  prevent  accidents. 
Chloroform  undergoes  decomposition  when  exposed  to  light  and  air,  hydro- 
chloric acid  and  chlorine  being  set  free  in  small  quantity.  These  can  affect 
the  course  of  anesthesia  only  through  their  local  irritant  action,  but  if  present 
in  sufficient  cjuantity  may  cause  the  respiration  to  be  more  irregular  than 
usual  in  the  earlier  stages;  the  chloroform  used  for  anaesthetic  purposes  ought, 
therefore,  to  be  kept  in  a  dark  place  or  in  colored  bottles.  Another  decom- 
position occurs  when  chloroform  is  evaporated  in  the  neighborhood  of  a  large 
flame,  such  as  that  from  gas  or  lamps,  and  hydrochloric  acid  and  carbonylchloride 
(CCI2O)  are  formed,  the  latter  being  a  gas  with  exceedingly  irritant  properties. 

Chloroform  is  a  heav}'  volatile  fluid,  of  characteristic  pleasant  odor  and  hot, 
sweetish  taste.  Its  specific  gravity  is  1.476  (U.  S.  P.)  and  1.483-1.487  (B.  P.), 
and  it  boils  at  60-61°  C.  A  number  of  tests  are  given  for  impurities,  but  those 
of  importance  can  generally  be  detected  by  the  odor,  especially  if  some  chloro- 
form is  allowed  to  evaporate  in  a  watch-glass,  when  the  last  drop  ought  to 
have  no  irritant  effect  when  inhaled.  Chlorine  and  hydrochloric  acid  may  be 
tested  for  by  shaking  the  chloroform  with  distilled  water,  and  testing  the  latter 
with  potassium  iodide  and  starch  and  with  silver  nitrate.  The  water  ought 
to  give  no  acid  reaction  to  litmus.  If  left  in  contact  with  concentrated  sulphuric 
acid,  cliloroform  should  not  become  darker  within  one  hour,  as  this  indicates 
the  presence  of  some  foreign  unstable  body.  The  other  impurities  require 
complicated  chemical  processes  for  their  detection. 

Ether  is  prepared  by  the  action  of  sulpluu'ic  acid  on  alcohol,  and  is  sub- 
secjuentlj'  purified  by  washing  with  water  and  alkalies.  It  seldom  contains 
impurities  of  importance.  J']ther  purificatus  (B.  P.)  or  .Ether  (U.  S.  P.)  is  a 
very  volatile  fluid,  of  a  suffocating,  irritant  odor  and  bitter  taste.    Its  specific 


ETHER  AND  CHLOROFORM  223 

gravity  is  0.716-0.717  (U.  S.  P.),  and  0.720  (B.  P.),  and  its  boiling  point 
is  35°  C.  It  evaporates  very  rapidly  in  the  air  and  should  leave  no  foreign 
odor  and  no  residue.  When  ether  has  been  exposed  to  air  and  sunlight  and  to  a 
varying  temperature,  it  may  contain  acetaldehyde  and  peroxide  bodies,  which 
render  it  more  irritant  to  the  mucous  membranes.  It  should  not  color  litmus 
paper,  nor  be  colored  within  an  hour  when  shaken  with  potassium  hydrate 
solution.  Ether  vapor  is  exceedingly  inflammable  when  mixed  with  air,  and 
it  should  therefore  be  kept  in  a  cool  place,  away  from  gas  flames  or  lamps. 

Ethyl  Chloride  is  obtained  by  the  action  of  hydrochloric  acid  on  alcohol,  and 
is  a  gas  at  normal  temperatures,  but  is  supplied  condensed  into  a  colorless  fluid 
with  a  pleasant  odor.  It  is  very  volatile,  inflammable  and  mobile,  and  is  liable 
to  contain  traces  of  the  same  impurities  as  have  been  mentioned  under  chloro- 
form.    It  should  be  kept  in  a  cool  place,  away  from  lights  or  fire. 

Bibliography  of  the  Anesthetics. 

The  literature  up  to  1880  is  given  in  Kappeler's  "Ansesthetica,"  Stuttgart,  1880. 

Dastre.    Les  Ansesthesiques,  Paris,  1890. 

Report  of  the  Hyderabad  Chloroform  Commission,  Bombay,  1891,  and  Lancet,  1890. 
The  criticisms  on  the  report  are  dealt  with  in  the  Lancet,  1890-91,  and  in  the  British 
Medical  Journal,  1890-91. 

MacWilliam.     Proc.  Roy.  Soc,  liii,  p.  464;    Journ.  of  Physiol.,  xxv,  p.  235. 

Cook  and  Briggs.     Johns  Hopkins  Hospital  Report,  xi,  p.  451. 

Blauel.     Beitrage  z.  klin.  Chir.,  xxxi,  p.  271. 

Embley.     Brit.  Med.  Journ.,  April,  1902.    Journ.  of  Phys.,  xxxii,  p.  147. 

Bayliss.     Proc.  Roy.  Soc,  B.,  Ixxx,  p.  365. 

Buckmaster  and  Gardner.    Proc.  Roy.  Soc,  B,  Ixxviii,  Ixxix,  Ixxxiv,  p.  347. 

Sherrington  and  Sowton,  Waller,  Horsley,  and  others.  Brit.  Med.  Journ.,  July  12, 
1902;  July  18,  1903;  July  23,  1904;  Sept.  24,  1904;   July  9,  1910. 

Loeb.     Arch.  f.  exp.  Path.  u.  Pharm.,  li,  p.  82. 

Schafer  and  Scharlieb.     Trans.  Roy.  Soc.  Edinb.,  xli  (ii),  p.  311. 

Pohl.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxviii,  p.  239. 

Ungar.       Vierteljahr.  f.  ger.  Med.,  xlvii,  p.  98. 

Kast  u.  Hester.  Zts.  f.  klin.  Med.,  xviii,  p.  469;  Zts.  f.  phys.  Chem.,  xi,  p.  277;  xii, 
p.  267. 

Ambrosius.     Virchow's  Archiv,  cxxxviii,  Suppl.,  p.  193. 

Lippmann.     Mittheil.  a.  d.  Grenzgebiet  der  Med.  u.  Chir.,  iv,  p.  21. 

Selbach.    Arch.  f.  exp.  Path.  u.  Pharm.,  xxxiv,  p.  1. 

Spenzer.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxiii,  p.  407. 

Rosenfeld.     Ibid.,  xxxvii,  p.  52. 

Dreser.  Beitrage  zur  khn.  Chirurg.,  x,  p.  412,  and  xii,  p.  353.  Arch,  f .  exp.  Path.  u. 
Pharm.,  xxxvii,  p.  375.     Bull.  Johns  Hopkins  Hosp.,  vi,  p.  7,  1895. 

Wells.     Journ.  Biol.  Chem.,  v,  p.  129. 

Howland  and  Richards.     Journ.  Exp.  Med.,  xi,  p.  344. 

Kemp.     New  York  Med.  Journ.,  1899,  ii,  p.  732. 

Thompson,  Buxton,  Levy.    Brit.  Med.  Journ.,  1900,  ii,  p.  883. 

Da  Costa.     American  Medicine,  May  18,  1901.    Annals  of  Surgery,  Sept..  1901. 

Snel.     Berlin,  klin.  Woch.,  1903,  p.  212. 

Braun.     Arch.  f.  klin.  Chirurg.,  Ixiv,  p.  201. 

Honigmann.     Arch.  f.  klin.  Chirurg.,  Iviii,  p.  730. 

Kionka.     Ibid.,  1,  p.  339. 

Pick.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlii,  p.  412. 

Elf  strand.     Ibid.,  xliii,  p.  435. 

Sackur.     Virchow's  Arch.,  cxxxiii,  p.  30.    (Pental.) 

Henderson.     Amer.  Journ.  of  Physiol.,  xxviii,  p.  275. 

Leuwen.     Arch.  f.  d.  ges.  Phys.,  cliv,  p.  307. 

Levy.     Heart,  1913,  iv,  p.  319. 

Burkhardt.     Arch.  f.  exp.  Path.,  Ixi,  p.  213. 

Madelung.     Ibid.,  Ixii,  p.  409. 

Zoepfel.     Arch.  £.  exp.  Path.  u.  Pharm.,  xlix,  p.  89.    (Ethyl  chlonde.) 

Cole.     Brit.  Med.  Journ.,  June  20,  1903.     (Ethyl  bromide.) 

McCardie.     Lancet,  April  4,  1903.     (Ethyl  chloride.) 

Embley.     Proc.  Roy.  Soc,  Ixxviii,  B.,  p.  391.    (Ethyl  chlonde.) 

Montgomery  and  Bland.     Journ.  of  Amer.  Med.  Assoc,  April  2,  1904.    (Ethyl  chlonde.) 


224  SUBSTANCES  ACTINa  AFTER  ABSORPTION 

3.  Nitrous  Oxide. 

The  oldest  of  the  aimesthetics,  nitrous  oxide,  N2O,  does  not  l)elong 
to  the  methane  series,  but  may  be  discussed  at  this  point. 

Symptoms. — AVhen  a  mixture  of  nitrous  oxide  and  air  is  inhaled 
for  a  few  seconds,  a  condition  resembling  alcoholic  intoxication  is 
produced,  with  much  hilarity  and  laughter,  so  that  the  oxide  is  known 
popularly  as  "laughing  gas."  Even  at  this  point  a  certain  amount 
of  aujesthesia  is  obtained,  and  it  was  the  observation  that  persons  fall- 
ing during  this  stage  did  not  complain  of  pain  that  first  suggested  to 
Wells  the  anfesthetic  properties  of  the  gas.  Davy  had  noted  these 
forty  years  ])reviously,  but  his  suggestion  that  nitrous  oxide  might  be 
used  in  surgical  operations  passed  unnoticed. 

The  inhalation  of  a  mixture  of  nitrous  oxide,  4  parts,  and  oxygen, 
1  part,  causes  after  a  few  seconds  a  rushing,  drumming,  hammering 
in  the  ears,  indistinct  sight,  and  a  feeling  of  warmth  and  comfort. 
The  movements  l)ecome  exaggerated  and  uncertain,  the  gait  is  stag- 
gering, and  the  body  sways  from  side  to  side.  The  patient  seems 
brighter  and  more  lively,  and  often  bursts  into  laughter.  Somewhat 
later  a  feeling  of  drowsiness  may  come  on,  but  this  is  not  constant; 
the  sensibility  to  pain  is  much  less  acute  than  normally,  but  no  com- 
plete anaesthesia  is  produced  by  this  mixture  of  gases;  the  sense  of 
touch  is  comparatively  little  altered,  and  total  unconsciousness  never 
results.  The  pupil  is  generally  slightly  dilated,  the  face  flushed,  and 
the  pulse  somewhat  accelerated. 

When  pure  nitrous  oxide  is  inhaled  without  the  admixture  of  oxygen, 
the  patient  passes  almost  instantaneously  through  the  symptoms 
already  described,  but  then  loses  consciousness  completely;  the  face  is 
cyanotic,  the  respiration  becomes  stertorous  and  dyspnoeic  and  ceases 
after  a  weak  convulsion,  while  the  heart  continues  to  beat  for  some 
time  afterwards.  If  the  mask  through  which  the  patient  has  been 
inhaling  the  gas  is  removed  when  the  cyanosis  becomes  marked,  very 
complete  anaesthesia  lasts  for  30-60  seconds,  and  the  patient  then 
recovers  within  a  few  minutes  and  suffers  from  no  after-effects  what- 
ever. No  prolonged  anaesthesia  can  be  produced,  however,  as  the 
respiration  becomes  endangered  if  the  mask  be  kept  on  longer  than  the 
beginning  of  the  cyanotic  stage. 

Action. — Nitrous  oxide  supports  combustion  outside  the  body,  for 
if  a  glowing  splinter  of  wood  be  held  in  it,  it  bursts  into  flame  exactly 
as  if  it  were  immersed  in  oxygen.  In  the  tissues  of  the  body,  however, 
nitrous  oxide  behaves  in  tlie  same  way  as  any  other  inditVerent  gas,  such 
as  hytlrogen  or  nitrogen;  that  is,  the  tissues  exposed  to  it  suffer  from 
asphyxia  owing  to  the  oxygen  of  the  air  being  excluded.  Thus*  plants 
do  not  grow  in  an  atmosphere  of  nitrous  oxide  and  seeds  do  not  germinate. 
Animals  die  aft<T  inhaling  nitrous  oxide  in  almost  the  same  time  as  after 
hydrogen  or  nitrogen,  and  at  death  the  spectrum  of  the  blood  shows 
no  oxyluemoglobin  to  be  present,  the  tissues  having  used  uj)  all  the 
availai)le  oxygen.       Nitrous  oxide,  therefore,  does  not  support  com- 


NITROUS  OXIDE  225 

bustioii  in  the  aiiiiiuil  body,  the  nitrogen  is  not  spht  ott"  from  the 
oxygen  at  body  temperature  as  it  is  when  the  oxide  is  exposed  to  high 
temperatures  outside  the  body. 

But  nitrous  oxide  has  a  special  effect  on  the  central  nervous  system, 
although  in  the  rest  of  the  tissues  it  acts  only  by  excluding  the  oxygen ; 
it  depresses  the  brain  by  virtue  of  its  molecular  form  just  as  chloroform 
or  ether  does.  This  has  been  shown  in  a  variety  of  ways;  thus,  if  it 
were  a  perfectly  indifferent  body  no  more  effect  would  be  produced  by 
it  when  mixed  with  one-fourth  of  its  volume  of  oxygen  than  by  air, 
which  consists  of  1  part  of  oxygen  and  4  parts  of  an  indifferent  gas, 
nitrogen.  But  80  per  cent,  nitrous  oxide  has  definite  effects  on  the 
behavior  of  animals,  as  has  been  mentioned,  and  even  73  per  cent, 
produces  some  slowing  of  the  respiration.  The  narcotic  action  was 
demonstrated  very  clearly  by  Paul  Bert  in  a  series  of  experiments  on 
man  and  animals.  He  noted  that  only  imperfect  antiesthesia  was  pro- 
duced by  80  per  cent,  nitrous  oxide,  while  the  pure  gas  produced  asphyxia. 
The  problem  was  to  introduce  as  much  gas  into  the  blood  as  would 
pass  in  under  pure  nitrous  oxide,  and  at  the  same  time  to  supply  sufficient 
oxygen  to  prevent  asphyxia.  The  absorption  of  nitrous  oxide  depends 
upon  its  partial  pressure  in  the  lungs,  as  it  is  simply  dissolved  in  the 
blood  without  forming  any  real  combination  with  it,  and  the  quantity 
absorbed  by  the  blood  may  be  augmented  by  increasing  the  barometric 
pressure.  Bert,  therefore,  administered  a  mixture  of  80  parts  nitrous 
oxide  and  20  parts  oxygen  to  animals  in  a  glass  case  in  which  the  pressure 
was  raised  one-fourth  above  the  ordinary  atmospheric  pressure.  The 
absorption  of  the  nitrous  oxide  was  the  same  as  if  the  animal  had 
breathed  the  pure  gas  at  the  ordinary  air  pressure,  and  at  the  same  time 
as  much  oxygen  was  absorbed  as  in  ordinary  air.  The  result  was  a 
complete  anjesthesia  without  asphyxia,  which  could  be  maintained  for 
three  days  without  injury  to  the  animal  (Martin).  Kemp  has  recently 
shown  that  mixtures  of  oxygen  and  nitrous  oxide  can  be  inhaled  for 
some  time  and  produce  anesthesia,  which  passes  off  at  once  when 
nitrogen  is  substituted  for  nitrous  oxide.  He  has  further  investigated 
the  blood  gases  during  nitrous  oxide  ana?sthesia,  and  finds  that_  the 
oxygen  contained  in  the  blood  at  the  deepest  stage  of  anaesthesia  is 
quite  sufficient  to  maintain  life  and  consciousness  were  no  nitrous  oxide 
present.  Again  Goltstein  found  that  frogs  were  narcotized  in  five  and 
one-half  minutes  in  an  atmosphere  of  nitrous  oxide,  in  one  and  one- 
quarter  hours  in  hydrogen,  and  showed  that  the  narcosis  and  death  in 
mammals  from  nitrous  oxide  differed  in  several  details  from  that  under 
indift'erent  gases.  There  can,  therefore,  be  no  dou])t  that  nitrous  ()xi(le 
has  distinct  effects  on  the  central  nervous  system,  although  it  is  nulill'er- 
ent  to  the  other  tissues.  The  ansesthesia  is  due  to  a  specific  action  on  the 
nervous  tissues  although  this  may  be  reinforced  by  the  asphyxia  present. 
And  Bert's  and  Martin's  experiments  would  indicate  that  death  occurs, 
not  from  the  direct  action  of  the  nitrous  oxide  on  the  respiratory  centre, 
but  from  the  lack  of  oxygen,  although  the  depression  of  the  centre  is 
undoubtedly  a  contributing  factor. 
15 


226  SUBSTANCES  ACTING  AFTER  ABSORPTION 

Tlie  same  question  arises  regarding  the  action  on  the  nerve  cells  as 
has  been  met  with  in  the  members  of  the  methane  series,  and  here 
again  the  preliminary  excitement  may  indicate  not  stimulation  of  the 
brain  areas,  but  lessened  activity  of  the  functions  of  control  and  restraint. 

The  respiratory  centre  is  depressed  when  the  gas  is  inhaled  in  com- 
paratively dilute  form,  for  Zuntz  and  Goltstein  found  the  breathing 
slower  and  deeper  after  73  per  cent.  The  respiration  ceases  some- 
what earlier  under  nitrous  oxide  than  under  indifferent  gases,  which 
would  indicate  that  the  cessation  of  the  breathing  is  due  at  any  rate 
in  part  to  the  specific  depressant  action.  In  asph\'xia  from  nitrous 
oxide  there  is  less  convulsive  movement  than  under  hydrogen,  owing 
to  the  general  depression  of  the  nerve  cells. 

The  circulation  is  little  affected  by  the  nitrous  oxide  directly,  the 
rise  in  the  blood-pressure  and  slowness  of  the  pulse  being  due  to  the 
asphyxial  condition  of  the  blood;  the  pulse  is  not  so  slow  as  in  ordinary 
asphyxia  or  in  asphyxia  from  nitrogen  or  hydrogen,  because  the  inhibi- 
tory centre  is  less  capable  of  activity.  The  heart  is  not  affected  directly, 
but  only  by  the  lack  of  oxygen. 

The  blood  dissolves  more  nitrous  oxide  than  water,  apparently 
because  it  is  taken  up  by  the  lipoids  of  the  corpuscles  in  the  same  way 
as  chloroform.  Nicloux  found  about  40  mgs.  in  100  c.c.  blood  at  the 
beginning  of  anaesthesia,  50  mgs.  in  complete  anaesthesia,  and  60  mgs. 
when  the  respiration  ceased. 

Nitrous  oxide  is  a  gas  at  ordinary  temperature  and  pressure,  and  is 
invariably  administered  by  inhalation  from  a  cylinder  into  which  it 
has  been  forced  under  high  pressure.  The  mask  generally  covers  both 
nose  and  mouth,  and  the  inhalation  is  carried  on  until  distinct  cyanosis 
appears,  when  the  anaesthesia  is  sufRcient  to  allow  of  short  operations, 
such  as  those  of  dentistry.  It  is  much  the  safest  of  the  anaesthetics, 
for  millions  of  persons  have  been  subjected  to  its  influence,  and  only 
a  few  cases  of  death  are  reported  from  its  use,  and  several  of  these  do 
not  seem  to  have  been  due  to  the  direct  action  of  the  gas. 

Ethyl  chloride  (see  p.  210)  has  been  introduced  as  a  substitute  for 
nitrous  oxide,  and  has  supplanted  it  to  a  certain  extent,  as  it  is  more 
easily  administered  and  the  apparatus  necessary  is  less  cumbrous. 
On  the  other  hand,  nitrous  oxide  is  responsible  for  much  fewer  accidents, 
rnfortunately,  the  anasthesia  cannot  be  kept  up  except  for  a  very  short 
time,  which  is  quite  insufficient  to  allow  of  ordinary  operative  pro- 
cedures. A  number  of  attempts  have  been  made  to  prolong  the  ana\s- 
thesia,  of  which  Bert's  was  nuich  the  most  successful.  The  operator, 
patient  and  attendants  were  enclosed  in  an  air-tight  chamber,  the 
air  pressure  was  raised  by  means  of  force  pumps,  and  Bert's  mixture  of 
oxygen  and  nitrous  oxide  was  inhaled  by  the  patient.  A  whole  series 
of  major  operations  were  performed  in  this  way,  the  anaesthesia  being 
coni|)lcl<'  as  long  as  was  desired,  and  the  patient  recovering  a  few  minutes 
after  tlie  mask  was  renio\-eil.  But  the  nu>thod  was  expensi\'e  and  the 
ai)paratus  cumbrous,  and  Bert  later  proi)osed  to  induce  anasthesia  by 
the  pure  gas  and  to  maintain  it  in  administering  alternately  pure  nitrous 


NITROUS  OXIDE  227 

oxide  and  nitrous  oxide  diluted  with  oxygen.  A  practical  method  of 
carrying  out  this  form  of  anaesthesia  has  been  devised  by  Hewitt,  whose 
apparatus  consists  essentially  of  two  reservoirs,  the  one  containing 
oxygen,  the  other  nitrous  oxide,  and  of  a  mixing  chamber  with  a  stop- 
cock by  which  the  proportion  of  oxygen  is  regulated.  The  inhalation 
is  commenced  with  pure  nitrous  oxide  or  with  a  mixture  containing 
only  2  per  cent,  of  oxygen.  When  anaesthesia  is  attained  the  percentage 
of  oxygen  is  increased  to  5-8  per  cent,  by  turning  the  stopcock,  and  the 
symptoms  determine  the  further  changes,  returning  consciousness 
necessitating  a  diminution  in  the  oxygen,  stertor  and  cyanosis  an 
increase.  This  form  of  anaesthesia  is  admirably  adapted  for  minor 
operations  and  has  been  maintained  in  some  cases  for  as  long  as  an  hour. 
The  circulation  and  respiration  are  less  seriously  altered  than  by  any 
other  method  that  induces  general  anfesthesia,  and  the  return  of  con- 
sciousness is  almost  immediate.  The  great  drawback  to  its  use  is  the 
cumbrous  apparatus  required  and  the  large  amount  of  gas  used,  amount- 
ing to  about  100  gallons  for  anaesthesia  of  half  an  hour.  Complete  mus- 
cular relaxation  is  seldom  attained  and  this  precludes  its  use  in  many 
operations,  in  which,  however,  it  may  be  employed  at  first  and  then  be 
replaced  by  chloroform  or  ether,  whose  preliminary  disagreeable  effects 
are  thus  avoided.  In  some  operations  80  per  cent,  nitrous  oxide  has  been 
used  after  partial  anaesthesia  had  been  attained  by  the  hypodermic 
injection  of  morphine  and  hyoscine,  and  the  results  have  been  favorable. 
Klikowitsch  proposed  the  use  of  80  per  cent,  nitrous  oxide,  not  for 
complete  anaesthesia,  but  to  relieve  pain  and  spasm  in  cases  of  asthma, 
in  labor  and  similar  conditions.  The  patient  could  inhale  it  if  neces- 
sary without  the  presence  of  a  medical  attendant,  and  it  had  the 
advantage  over  the  other  depressants  that  it  need  only  be  inhaled 
when  an  attack  of  pain  was  approaching  and  that  it  left  no  depression 
afterward.  But  80  per  cent,  is  apt  to  induce  symptoms  closely  resemb- 
ling those  of  alcoholic  intoxication. 

The  high  blood-pressure  induced  by  nitrous  oxide  asphyxia  is  some- 
times said  to  be  dangerous  in  elderly  persons  from  their  liability  to 
apoplexy,  and  of  the  few  fatalities  under  the  gas  several  would  seem 
due  rather  to  this  than  to  the  drug  directly,  but  the  danger  is  often 
overstated,  and,  in  fact,  it  is  a  question  whether  the  shock  caused  by 
the  operation  without  gas  would  not  be  more  dangerous  than  the  effects 
of  the  gas  itself.  No  such  symptoms  arise  when  the  nitrous  oxide  is 
diluted  with  oxygen  as  in  Hewitt's  method. 

Occasionally  some  glycosuria  occurs  after  the  inhalation,  not  owing 
to  the  gas  itself,  but  to  the  accompanying  asphyxia.  It  is  merely 
temporary  and  has  no  practical  importance. 

The  treatment  of  accidents  in  anaesthesia  under  nitrous  oxide  con- 
sists in  artificial  respiration  alone. 

Bibliography. 

Paul  Bert.     Comptes  rendus,  Ixxxvii,  p/  728,  and  xcvi,  p.  1271. 
Hermann.     Arch.  f.  Anat.  uiid  Phys.,  1864,  p.  521. 
Jolyet  et  Blanche.     Arch,  de  Phys.,  1873,  p.  364. 


22S  SUBSTANCES  ACTINd  AFTER  ABSORPTION 

Goltstein.     Pfluger's  Arch.,  xvii,  p.  331. 

Klikowilsch.     Virchow's  Arch.,  xciv,  p.  148.     (Literature.) 

Martin.     Comptes  rendus,  cvi,  p.  290. 

Van  Arsdale.     Ana.  Journ.  Med.  Sciences,  cii,  p.  131. 

Wood.     Dental  Cosmos,  1893. 

Kemp.     Brit.  Med.  Journ.,  1897,  ii,  p.  1480. 

Hewitt.     Anirsthetics  and  their  administration,  London,  1900. 

4.     Soporifics.—Chloral  Group. 

Some  twenty  years  after  the  introduction  of  the  anaesthetics,  a  new 
interest  was  given  to  the  methane  series  by  the  examination  of  chloral 
hydrate  (CClsCIICOII),)  by  Liebreich.  Henceforth  the  attention  of 
investigators  was  diverted  from  the  quest  of  anaesthetics  to  that  of 
hypnotics,  with  the  result  that  a  number  of  valuable  drugs  have  been 
added  to  therapeutics.  These  soporifics,  or  narcotics,  have  the  same 
general  action  as  the  anaesthetics,  but  are  used  only  to  produce  the  first 
effects  of  imperfect  consciousness  or  sleep.  The  antesthetics  might  be 
used  for  this  purpose  were  it  not  for  the  comparatively  short  time 
during  which  their  action  persists.  Narcotics  are  required  to  produce 
a  slight  but  lasting  effect,  and  for  this  purpose  the  gradual  absorption 
from  the  stomach  is  better  adapted  than  the  rapid  absorption  and 
equally  rapid  elimination  by  the  lungs.  The  narcotics  are,  therefore, 
less  volatile  than  the  anesthetics,  and  ought  to  be  soluble  in  water  and 
not  irritant  in  the  stomach,  so  as  to  permit  of  rapid  absorption.  The 
most  widely  used  members  of  this  group  are  chloral,  yaraldehydc ,  suJ- 
phonal  (Did  veronal,  but  many  others  have  received  attention.  They 
all  resemble  each  other  in  their  general  soporific  action,  and  that  of 
chloral  may  be  taken  as  typical  of  all;  in  their  other  characters  some 
differences  are  presented  and  these  will  be  taken  up  for  each  individual 
drug. 

Symptoms. — Chloral  in  15-30  gr.  doses  produces  drowsiness  and 
weariness,  which  soon  pass  into  a  condition  resembling  natural  sleep 
very  closely,  from  which  the  patient  can  be  awakened  by  ordinary 
means,  such  as  touching,  loud  .sounds,  or  pain.  The  respiration  and 
pulse  are  somewhat  slower  than  in  waking  moments,  l)ut  scarcely  more 
so  than  in  natural  sleep,  and  the  somewhat  narrowed  pupil  antl  unal- 
tered excitability  of  the  reflexes  are  also  common  to  both  conditions.  As 
a  general  rule,  the  sleep  passes  off  in  five  to  eight  hours  and  leaves  no 
un])lcasant  results,  but  sometimes  headache,  giddiness,  and  confusion 
are  complained  of.  Occasionally  no  real  sleej)  is  i)roduced  by  chloral, 
a  condition  exactly  resembling  alcoholic  intoxication  following  its 
administration  and  continuing  for  some  time. 

When  larger  (juantities  (75  grs.)  are  taken,  the  sleep  is  much  deeper, 
the  patii'iit  cannot  be  arou.sed  to  complete  consciousness,  the  reflexes 
are  distinctly  lessened  and  the  sensation  of  j)ain  is  less  acute,  although 
no  coni|)lete  ana'sthesia  is  ])resent.  The  respirations  are  fewer  and  the 
pulse  may  be  slow  aufl  somewliiit  weak.  The  sleep  lasts  \ cry  nnich  longer 
(ten  to  fifteen  hours), and  nausea,  \-onuting,  headacheand  confusion  oft(Mi 
remain  after  con.sciousness  is  regained.      In  still  larger  (juantities  chloral 


SOPORIFICS— CHLORAL  GROUP  229 

produces  a  condition  resembling  exactly  the  third  stage  of  anaesthesia. 
The  reflexes  are  entirely  absent  and  no  movement  is  elicited  by  painful 
operations,  the  muscles  are  completely  relaxefl,  the  respiration  and 
pulse  are  both  slow  and  weak,  and  eventually  asphyxia  occurs  from 
paralysis  of  the  respiratory  centre.  The  heart  continues  to  beat  for  a 
short  time  after  the  breathing  ceases. 

The  first  stage  is  the  only  one  elicited  in  therapeutics.  The  use  of 
chloral  as  an  anesthetic  in  man  would  be  quite  unjustifiable,  because 
it  is  impossible  to  adjust  the  dose  accurately  enough  to  allow  of  com- 
plete anaesthesia  without  danger  of  respiratory  failure. 

Action.^ — The  Central  Nervous  System  is  depressed  and  eventually 
completely  paralyzed  by  chloral  and  its  allies.  Unlike  the  anaesthetics 
and  alcohol,  however,  chloral  rarely  causes  excitement,  but  this  may 
be  due  to  the  facts  that  the  surroundings  of  the  patient  are  less  likely 
to  cause  excitement  and  that  the  drug  itself  causes  less  local  irritation. 
The  results  of  psychological  experiments  on  the  effects  of  small  doses 
of  the  narcotics  seem  to  indicate  that  they  all  depress  the  sensory  or 
receptive  functions  of  the  brain,  while  its  motor  activity  is  much 
reduced  by  chloral  and  sulphonal,  but  may  appear  to  he  actually 
increased  by  paraldehyde;  this  apparent  stimulation  is  analogous  to 
that  under  alcohol  and  may  be  explained  by  lessened  control.  The 
sleep  induced  by  the  dulling  of  the  perceptions  may  be  interrupted  by 
more  intense  stimuli  from  without.  In  particular,  acute  pain  may 
prevent  sleep  after  chloral,  which  seems  to  have  no  specific  effects  on 
pain  sensation  such  as  is  possessed  by  morphine.  In  larger  quantities, 
however,  even  very  great  disturbance  of  the  environment  produces  no 
interruption  of  the  sleep,  and  the  reflex  response  to  irritation  is  very 
much  lowered.  The  motor  areas  of  the  brain  cortex  are  rendered  less 
irritable  by  chloral,  and  eventually  fail  to  react  to  the  strongest  electrical 
stimulation.  The  reflexes  of  the  spinal  cord  are  depressed  and  finally 
paralyzed  before  the  failure  of  the  respiration;  this  depressant  action  on 
the  spinal  reflexes  is  much  more  marked  than  that  seen  under  morphine. 
The  last  part  of  the  central  nervous  system  to  be  attacked  is  the  medulla 
oblongata,  for  although  the  respiration  is  somewhat  slower  and  shallower 
after  small  quantities,  it  is  scarcely  more  affected  than  in  ordinary 
sleep,  and  Loewy  found  that  both  the  excitability  of  the  centre  and  the 
volume  of  the  inspired  air  were  very  similar  in  the  two  conditions. 
As  the  dose  is  increased,  however,  the  respiration  becomes  very  slow 
and  weak,  and  finally  ceases  from  paralysis  of  the  centre. 

The  heart  is  somewhat  slower  after  chloral  in  moderate  doses,  but 
scarcely  more  so  than  in  natural  sleep.  There  is  often  some  flushing 
of  the  face  and  head  from  some  obscure  central  action,  but  the  blood- 
pressure  is  little  affected  in  the  therapeutic  use  of  the  drug.  In  poisoning, 
the  blood-pressure  is  reduced  by  weakness  of  the  vasomotor  centre  and 
of  the  heart,  the  latter  manifesting  itself  also  in  slowing  of  the  pulse. 
This  action  on  the  circulation  from  poisonous  doses  is  more  evident 
under  chloral  than  under  the  other  hypnotics  which  do  not  contain 
chlorine.     The  same  difference  is  met  with  in  ether  and  chloroform, 


230  SUBSTANCES  ACTING  AFTER  ABSORPTION 

of  wliich  the  latter  affects  the  circulation  more  strongly.  And  the 
action  on  the  heart  in  chloral  poisoning  resembles  that  of  chloroform, 
the  auricles  heing  affected  sooner  than  the  ventricles  and  the  strength 
of  contraction  falling  more  than  the  rate. 

Locally,  chloral  has  an  irritant  action  when  applied  in  concentrated 
solution  and  this  leads  occasionally  to  nausea  and  vomiting  when  it  is 
prescribetl  with  insufficient  fluid.  This  irritant  action  induces  red- 
ness and  even  vesication  when  chloral  is  applied  to  the  skin;  it  is  said 
to  corrode  when  applied  to  unprotected  surfaces,  and  certainly  possesses 
antiseptic  properties  like  chloroform.  It  is  rapidly  absorbed  when 
given  by  the  mouth  and  is  carried  to  the  central  nervous  system  where 
it  is  taken  up  by  the  cells  until  they  contain  more  than  the  blood  cor- 
puscles or  the  cells  of  other  organs,  such  as  the  liver.  Liebreich  intro- 
duced chloral  as  a  hypnotic  in  the  belief  that  it  was  decomposed  in 
the  blood  and  chloroform  liberated,  but  this  has  been  shown  to  be 
erroneous,  no  chloroform  being  found  in  the  blood  or  expired  air  after 
chloral.  Chloral  has  no  action  on  muscle  or  nerve  in  the  living  animal, 
but  when  it  is  applied  to  the  exposed  nerve  it  first  irritates  and  later 
paralyzes  it,  and  injected  directly  into  the  artery  of  a  muscle  it  causes 
immediate  rigor.  The  temperature  falls  after  the  administration  of 
chloral  from  the  lessened  muscular  movement,  and  perhaps  from  the 
increased  output  of  heat  through  the  dilated  skin  vessels. 

The  effects  of  chloral  on  the  tissue-change  have  been  found  to  corre- 
spond very  closely  to  those  of  chloroform.  Thus  fatty  degeneration 
of  various  organs  has  been  produced  by  the  prolonged  administration 
of  chloral  and  its  compounds,  and  the  increase  in  the  nitrogen,  phos- 
phates and  sulphur,  especially  of  the  unoxidized  sulphur,  in  the  urine 
points  to  augmented  destruction  of  the  proteins  of  the  body,  together 
with  imperfect  oxidation.  The  acidity  of  the  urine  is  much  increased 
by  the  presence  of  urochloralic  acid.  Chloral  was  formerly  supposed  to 
lead  to  glycosuria,  but  this  has  been  shown  to  be  erroneous,  the  reducing 
substance  in  the  urine  being  urochloralic  acid,  and  not  sugar.  In 
addition  to  this  effect  on  the  tissues  generally,  less  oxygen  is  absorbed 
and  less  carbonic  acid  excreted  owing  to  the  diminished  muscular 
movement. 

Chloral  is  reduced  in  the  tissues  to  trichlorethyl  alcohol  (CCI3CH2- 
Oli),  which  combines  with  glycuronic  acid  to  form  urochloralic  acid, 
and  is  excreted  in  this  form  in  the  urine.  Some  escapes  by  the  kidneys 
unchanged,  however,  and  some  is  thrown  into  the  stomach,  and  this 
may  account  for  the  nausea  and  discomfort  felt  after  awaking  in  some 
cases. 

The  other  hypnotics  of  this  series,  with  the  exception  of  chloralose, 
correspond  exactly  with  chloral  as  far  as  their  action  on  the  central 
nervous  sy.stem  is  concerned.  The  chief  difference  in  their  effects 
is  seen  in  the  circulation  and  metabolism,  which  are  comparatively 
little  affected  by  those  which  do  not  possess  substituted  chlorine 
atoms. 


SOPORIFICS— CHLORAL  GROUP  231 

Paraldehyde  (CgHioOs),  a  polymer  of  etliylaldehyde,  resembles  alcohol 
in  its  effects  though  it  is  a  much  more  powerful  narcotic  and  rarely  induces 
any  s\'mptoms  of  excitement.  It  does  not  affect  the  heart  directly 
even  in  large  doses  and  has  no  such  effects  on  the  protein  metabolism 
as  have  been  observed  under  the  prolonged  administration  ()f  chloral; 
the  pulse  is  slightly  slower  and  the  carbonic  acid  exhaled  is  less  than 
normally,  but  these  changes  are  due  to  the  muscular  movements  being 
lessened,  and  are  hardly  greater  in  extent  than  occur  in  natural  sleep. 
Very  large  quantities  have  been  taken  without  fatal  results,  and  in 
fact  without  any  more  serious  consequences  than  prolonged  uncon- 
sciousness. Paraldehyde,  however,  has  a  most  unpleasant  odor  and  a 
hot,  burning  taste,  which  renders  its  administration  somewhat  difficult. 
In  addition  it  is  excreted  in  part  by  the  lungs,  though  mainly  in  the  urine, 
and  the  odor  remains  in  the  breath  for  some  time  after  the  patient 
awakens. 

Sulphonal  ((CH.02C(SO2C2H6)2)  and  its  allies,  Trional  ((CaHsCHsC- 
(S0An5)o)  and  Tetronal  ((C2H5)2C(S02C2H5)2),  have  no  immediate 
action  on  the  circulation  even  in  large  doses,  though  it  is  stated  that 
their  prolonged  use  is  deleterious  to  the  heart,  and  they  appear  to  be 
more  uncertain  in  their  narcotic  action  in  cases  of  heart  disease  than  in 
other  conditions.  They  are  practically  tasteless  powders,  and  are 
therefore  easily  taken,  but  their  insolubility  in  water  renders  their 
absorption  slow  and  uncertain,  and  sleep  is  therefore  late  in  following 
their  administration,  while,  on  the  other  hand,  depression,  drowsiness 
and  lack  of  energy  are  often  complained  of  the  day  after.  There  is 
some  evidence  that  they  exercise  a  deleterious  effect  on  the  liver,  for  the 
relation  of  urea  to  the  total  nitrogen  of  the  urine  is  changed  and  the 
metabolism  of  the  purine  bodies  is  also  affected. 

The  use  of  the  sulphonal  group,  especially  wdien  prolonged,  has  led 
in  many  cases  to  a  series  of  symptoms,  the  most  characteristic  of  which 
is  the  appearance  in  the  urine  of  a  reddish-brown  pigment,  hsemato- 
porphyrin,  an  iron-free  product  of  the  decomposition  of  haemoglobin. 
This  occurs  most  frequently  in  anemic  women,  and  is  accompanied  by 
constipation,  pain  in  the  stomach  region  and  vomiting,  weakness  and 
ataxia,  confusion  and  partial  paralysis,  and  eventually  by  suppression 
of  the  urine  or  by  collapse  and  death.  These  symptoms  may  appear 
several  days  after  a  single  dose,  sometimes  after  an  interval  of  one  or 
two  weeks.  The  excretion  of  hsematoporphyrin  in  the  urine  appears 
due  to  some  obscure  change  in  the  liver;  it  occurs  in  traces  in  the  rabbit's 
urine  normally  and  in  larger  quantities  after  the  animal  has  been  treated 
with  sulphonal  (Neubauer).  In  other  animals  the  prolonged  adminis- 
tration of  sulphonal  often  causes  albumin  and  casts  in  the  urine,  while 
haemorrhages  in  the  kidneys  have  been  produced  in  them  by  the  adminis- 
tration of  only  a  few  doses.  The  amount  of  ha?matoporphyrin  in  the 
urine  is  sometimes  very  large;  in  one  case  Tyson  and  Croftan  found 
that  the  quantity  passed  in  one  day  indicated  the  destruction  of  one- 
seventeenth  of  the  total  haemoglobin  of  the  body.  Very  large  doses 
are  said  to  produce  convulsive  movements  in  animals,  wdiile  ordmary 


232  SUBSTANCES  ACTING  AFTER  ABSORPTION 

OIK'S  cause  sleep  and  subsequent  drowsiness.  Sulphonal  is  decomposd 
in  the  body  and  is  excreted  larfjely  as  ethylsulphonic  acid  in  the  urine, 
in  which  traces  of  the  unchanged  substance  have  also  been  found.  The 
decomposition  is  a  slow  process,  however,  for  Kast  found  sulphonal  in 
the  blood  many  hours  after  its  administration.  The  ethylsuli)honic 
acid  seems  to  have  no  action  whatever  in  itself,  so  that  the  narcosis  is 
due  to  the  unchanged  molecule  of  sulphonal. 

Veronal,  dirthyll)arbituric  acid  ((C2H5).C(CONH)2C()),  and  its  sodium 
salt,  tiii'dittdl  (XaC8lIu()3N2),  seem  to  be  devoid  of  action  except  on  the 
central  nervous  system,  and  thus  approach  the  ideal  more  closely  than 
any  of  the  others.  In  ordinary  doses  (5-10  grs.)  they  induce  natural 
sleep  without  subseciuent  depression,  and  larger  quantities  deepen  and 
lengthen  the  unconsciousness  without  other  organs  than  the  central 
nervous  system  being  involved,  though  the  patient  may  complain  of 
lethargy  and  drowsiness  subsequently.  Fatal  poisoning  has  occurred 
from  very  large  quantities  {e.  g.,  150  grs.),  the  sleep  passing  into  coma, 
ending  in  respiratory  failure.  From  50-90  per  cent,  has  been  recovered 
unchanged  from  the  urine,  the  rest  apparently  undergoing  oxidation  in 
the  tissues.  They  act  as  hypnotics  in  smaller  quantities  than  any  of 
the  others  of  this  series.  In  some  animals  veronal  causes  increased 
reHexes  and  even  general  convulsions,  but  this  efi'ect  has  not  been  seen 
in  man. 

Butylchloral,  or  Crotonchloral  (C3H4Cl3CH(OH)2),  was  said  by  Liebreich 
to  possess  a  specific  analgesic  action  on  the  nerves  of  the  face  and  head, 
but  this  has  been  shown  to  be  incorrect  and,  as  its  effects  are  identical 
with  tliose  of  chloral  in  almost  all  respects,  crotonchloral  seems  entirely 
superduous. 

Chloralamide,  or  cliloralfonnaniide  (CCUCHOH-NHCHO),  was  introduced 
as  tending  to  depress  the  heart  less  than  chloral,  but  this  has  not  been  demon- 
strated. It  is  said  to  be  less  irritant  than  chloral  in  the  stomach,  but  to  be 
somewhat  slower  and  less  certain  in  its  effects.  Chloral  is  formed  by  its  de- 
composition in  the  bod}^,  and  is  excreted  as  urochloralic  acid,  and  fatt}^  degener- 
ation has  been  observed  after  its  prolonged  administration. 

Chloralose  (CarinCbOc),  a  sugar  compound  of  cliloral,  acts  nuich  more  like 
morpliiue  than  like  chloral,  depressing  the  psychical  functions,  while  increasing 
the  reflexes  until  convulsions  rescmbhng  those  of  strychnine  may  be  produced. 
The  heart  is  comparatively  little  aifected,  and  the  respiration  remains  strong 
unless  very  large  doses  are  given.  In  man  it  induces  sleep,  which  is  sometimes 
attended  by  distinctly  exaggerated  reflexes,  however,  especially  when  large 
doses  are  given. 

Amylene  Hydrate,  or  dimethylethylcarbinol  ((CH3)2COHCH-2Cll3),  is  closely 
allied  to  paialdchyde  in  its  elTects  but  is  twice  or  thrice  as  powerful, 
while  it  is  only  one-half  as  strong  as  chloral.  It  is  said  to  depress  the  heart 
more  than  ))arald(!hyde,  but  less  than  cliloral,  and  to  produce  excitement  and 
convulsions  in  tiie  carnivora,  but  not  in  the  herbivora.  Even  in  man,  it  causes 
excitement  mon;  frecjuently  than  most  other  soporiflcs,  and  Ilarnack  and 
Meyer  stale  that  it  first  stinuilates  and  then  depresses  the  respiratory  centre 
as  well  as  other  parts  of  the  central  nervous  system,  and  that  it  induces  a  very 
marke(l  fall  in  the  temperature.  It  has  little  or  no  effect  on  the  general  meta- 
bolism, and  is  excreted  in  the  urine  in  combination  with  glycuronic  acid  in  the 
rai)l)it,  hut  is  exhaled  by  the  lungs  for  the  most  i)art  by  the  dog  and  possibly 
bv  man.    It  is  less  certain  in  its  action  than  chloral  l)ut  has  not  received  so  wide 


SOPORIFICS— CHLORAL  GROUP  233 

a  trial  as  it  would  seem  to  merit.  A  coniiiiiiation  of  chloral  and  amyleuc  hydrate 
has  been  introduced  under  the  name  of  Dormiol,  l)ut  offers  no  advantages  over 
chloral. 

Urethane,  or  ethyl  carbamic  ester  (CONH2OC2H5),  is  too  weak  and  inconstant 
in  its  action  in  man  to  be  satisfactory.  In  many  cases  it  is  an  almost  perfect 
hypnotic,  easily  taken  in  solution,  producing  Hght  sleep  with  no  after-effects, 
but  in  others  it  seems  to  have  httle  or  no  hypnotic  effect.  It  is  oxidized  in  the 
body  to  urea.  Hedonal,  the  amyl  carbamic  ester  (CONH-20C5Hii),  appears  to 
have  a  greater  hypnotic  effect  than  urethane,  but  also  fails  to  induce  sleep 
in  a  considerable  proportion  of  cases.  It  is  followed  by  no  after-effects  and  is 
oxidized  in  the  body  in  the  same  way  as  urethane. 

Bromoform,  (CHBrs)  has  aneesthetic  properties  like  chloroform,  but  is  not 
volatile  enough  for  inhalation.  Of  late  years  it  has  been  used  internally  in 
whooping-cough,  and  in  this  relation  it  is  important  to  remember  that  it  gives 
rise  to  fatty  degeneration  when  taken  continuously.  A  number  of  cases  of 
alarming  poisoning  in  children  have  been  recorded  from  its  use.  It  has  also 
been  used  occasionally  in  insomnia. 

Bromal  (CBrsCOH)  differs  in  several  respects  from  chloral  in  its  action. 
In  animals  its  injection  is  followed  by  restlessness  and  excitement,  aiid  then 
by  stupor,  which  is  often  accompanied  by  dyspnoea,  and  ends  in  failure  of 
the  respiration,  or  in  convulsions.  The  pupil  is  much  contracted,  and  profuse 
salivation  is  observed.  It  acts  on  the  heart  like  chloral  but  is  much  more  poison- 
ous, and  is  scarcelv  used  in  therapeutics. 

Chloretone,  triclilorpseudobutylalcohol  (CCl3C(CH3)20H),  resembles  chloral 
in  most  respects,  but  is  less  hable  to  irritate  the  stomach.  Very  large  doses 
have  been  swallowed  without  producing  any  untoward  symptoms,  but  the 
hypnotic  effect  is  obtained  by  the  use  of  smaller  doses  than  are  necessary  in 
the  case  of  chloral.  Like  chloral,  chloretone  has  some  virtues  as  an  antiseptic, 
and  in  addition  it  paralyzes  the  terminations  of  the  sensory  nerves  when  it  is 
apphed  locally  and  has  proved  of  value  as  a  local  anaesthetic. 

Isopral,  the  triclilorisopropylalcohol  (CCI3CHCH3OH),  resembles  chloretone 
closely. 

Many  other  similar  bodies  have  been  introduced  as  hypnotics,  but  have 
not  proved  to  possess  any  advantages  over  those  already  enumerated.  Among 
these  are  hypnone  (CeHsCOCH^),  neuronal  ((C2H5)2BrCCONH2),  bromural, 
and  brometone. 

Tolerance  is  soon  acquired  for  each  of  these  drugs,  and  when  it  is 
developed  for  one,  large  doses  of  any  of  the  others  are  required  in 
order  to  produce  sleep.  Tolerance  for  alcohol  also  involves  the  use  of 
larger  quantities  of  the  hypnotics,  and  in  fact  often  leads  to  the  com- 
plete failure  of  any  except  the  most  powerful. 

Not  infrequently  the  hypnotics  lead  to  skin  eruptions,  especially 
when  used  for  some  time.  These  assume  various  forms,  the  most 
common  being  of  the  erythema  order,  but  among  others  urticaria,  pur- 
pura, papular  eruptions  and  blisters  occur. 

Habit. — Prolonged  abuse  of  chloral  leads  to  a  condition  somewhat 
resembling  that  seen  in  chronic  alcoholism  or  morphinism,  and  marked 
by  general  depression  and  cachexia,  with  impairment  of  the  mental 
powers,  digestive  disturbance  and  exanthemata.  The  sudden  with- 
drawal of  the  drug  in  these  cases  has  sometimes  led  to  symptoms 
resembling  those  of  delirium  tremens.  Cases  of  sulphonal  and  veronal 
habit  have  also  been  reported  with  symptoms  resembling  those  of  the 
chloral  habit. 


234  SUBSTANCES  ACTING  AFTER  ABSORPTION 


Preparations. 

Chloralum  IIydratum  (U.  S.  P.),  Chloral  Hydras  (B.  P.)  (CCl3CH(OH)2 
or  (CCI3COH+H2O),  a  ciystalliue  solid,  of  a  characteristic  pungent  odor,  and 
hot,  acrid  taste,  readily  sohible  in  water,  alcohol,  ether  and  oils,  is  almost 
invariably  prescribed  in  dilute  solution  in  syrup.  Its  deliquescent  properties 
preclude  its  use  in  most  of  the  solid  preparations,  and  its  irritant  effects  contra- 
indicate  hypodermic  injection.  Dose,  1  G.  (15  grs.);  B.  P.,  5-20  grs.,  which 
may  be  repeated  if  necessal'y,  in  one  or  two  hours. 

Syrupus  Chloral  (B.  P.)  (20  per  cent.),  ^-2  fl.  drs. 

Paraldehydum  (U.  S.  P.,  B.  P.)  (C6H12O3)  a  colorless  fluid  of  strong,  char- 
acteristic odor  and  burning  taste.  It  may  be  prescribed  in  brandy  and  water, 
or  in  water  up  to  10  per  cent.,  or  in  capsules.  2  c.c.  (30  mins.);  B.  P.,  ^-2  fl. 
drs. 

Barbitonum  (B.  p.),  Veronal  (C2H6)2C(C0NH)2C0,  colorless  crystals  with 
a  faint  bitter  taste,  soluble  in  145  parts  of  water;  prescribed  in  powders  or 
tablets,  to  be  dissolved  in  warm  water  or  milk.    Dose,  0.3-0.5  G.     (5-8  grs.). 

SULPHONAL     (B.   P.),     SuLPHONMETHANUM     (U.    S.    p.)     ((CH3)2C(S02C2H6)2), 

a  crystalline  powder,  without  taste  or  odor.  It  may  be  prescribed  in  powder 
form  to  be  taken  one  to  two  hours  before  retiring,  but  is  soluble  in  hot  water 
or  milk,  and  when  given  in  solution  acts  more  rapidly  and  leaves  less  confusion 
afterward.    It  is  prescribed  in  doses  of  1  G.  (15  grs.) ;  B.  P.  10-30  grs. 

Sulphonethylmethanum  (U.  S.  P.),  Methylsulphonal  (B.  P.),  Trional  (CH3'C2H5*- 
C'(S02C2H6)2)  resembles  sulphonal.  but  is  more  soluble  and  has  a  bitter  taste. 
1  G.  (15  grs.);  B.  P.,  10-20  grs. 

JEthylis  Carbamas  (U.  S.  P.),  urethane  (CO'OC2H5'NH2),  colorless  crj^stals, 
odorless,  with  a  cool,  saline  taste,  very  soluble  in  water,  alcohol,  and  ether. 
Dose,  1-5  G.  (15-75  grs.).    U.  S.  P.,  1  G.  (15  grs.). 

Bromoforrnum  (U.  S.  P.)  (CHBrs),  a  heavy,  transparent,  colorless  liquid  with 
an  ethereal  odor  and  a  taste  like  that  of  chloroform,  very  little  soluble  in 
water,  but  readily  soluble  in  alcohol.     Dose,  0.2  c.c.  (3  mins.). 

Chloraljormamidum  (U.  S.  P.),  Chloral  Formamidum  (B.  P.),  or  chloralamide 
(CClsCHOHNH-COH),  a  wliite  crystaUine  powder  with  a  faintly  bitter  taste; 
prescribed  in  powder  or  in  solution  in  water  or  spirit.  Dose,  1  G.  (15  grs.).; 
B.  P.,  15^5  grs. 

Unofficial. 

Tetronal  resembles  sulphonal  closely,  and  may  be  prescribed  in  the  same 
dose  and  form. 

Medinal  or  sodium  veronal,  a  white  crystalline  powder  soluble  in  5  parts 
of  water  with  a  bitter  alkaline  taste.    Dose  0.3-0.6  G.  (5-10  grs.)  in  water. 

Aimjleni  Hydras  ( (CH3)2COHCH2CH2),  a  colorless  liquid  of  pungent  taste, 
and  of  an  odor  somewhat  resembling  camphor.  It  maj^  be  prescribed  in  capsules, 
or  up  to  10  per  cent,  in  water.    Dose,  3-5  c.c.  (40-80  mins.). 

Iledonal,  a  crj'stalline  powder  with  a  taste  resembling  that  of  menthol,  very 
sliglitly  soluble  in  water.    Dose,  2  G.  (30  grs.)  in  powder  or  tablets. 

CIdoretone  (CCl3C(CH2)30H),  colorless  crystals  with  a  strong  camphora- 
ceous  odor,  slightly  soluble  in  water,  verj'^  soluble  in  alcohol;  it  may  be  pre- 
scribed in  tablets.    Dose,  0.3-1  G,  (5-15  grs.). 

Proponal  differs  from  veronal  only  in  having  propyl  substituted  for  ethyl, 
and  is  used  in  the  same  dose. 

Isopral  (C2li3Cl3CHOiI),  white  crystals  with  a  camphoraceous  odor  and 
aromatic  biting  taste,  soluble  in  30  parts  of  water;  prescribed  in  doses  of  0.5- 
0.75  G.  (5-8  grs.) 

Therapeutic  Uses. — In  ordinary  jiractice  cliloral  and  veronal  are  the 
be.sl  of  the  ^roup.  Sulplional  and  its  allies  should  he  avoided  on  aeeonnt 
of    their    capricious    poi.sonons    action.      Parahh'hyde    is    disa^rcH'ahie 


SOPORIFICS— CHLORAL  GROUP  235 

but  has  been  advised  as  a  substitute  for  chloral  in  cases  where  there  is 
a  tendenc}^  to  form  the  habit,  as  here  its  disagreeable  properties  are 
of  advantage.  Other  drugs  which  are  used  to  cause  sleep  are  opium  and 
morphine,  cannabis  indica,  alcohol,  bromides,  and  hyoscine. 

The  hypnotics  are  chiefly  used  to  produce  rest  and  sleep  in  cases 
of  insomnia,  and  in  almost  every  form  of  nervous  excitement.  Until 
the  discovery  of  the  therapeutic  value  of  chloral,  opium  was  used 
in  most  of  these  cases,  and  when  sleeplessness  is  due  to  pain  it  is  still 
preferable  to  the  more  modern  remedies,  which  have  comparatively 
slight  influence  on  acute  pain,  except  in  very  large  doses.  But  in 
delirium,  mania  and  convulsions  of  various  kinds,  their  action  on  the 
nerve  centres  is  preferable  to  that  of  opium,  especially  where  these 
convulsions  are  of  spinal  origin  or  of  a  reflex  nature;  thus,  in  strych- 
nine poisoning  and  in  tetanus,  chloral  is  of  great  value,  although  in 
the  former  it  may  have  to  be  reinforced  by  chloroform  during  the 
convulsions.  In  delirium  from  fever  or  from  ursemic  intoxication  and 
similar  causes,  comparatively  small  doses  often  produce  most  satis- 
factory results,  and  in  various  spasmodic  affections,  such  as  cough, 
asthma  and  choreic  movements,  it  is  exceedingly  useful.  Chloral  has 
also  been  advised  to  lessen  the  pains  of  labor. 

Most  of  the  soporifics  have  been  used  more  or  less  extensively  as 
hypnotics  in  simple  insomnia  and  in  insanity,  but  when  the  disturb- 
ance assumes  a  more  violent  character  there  is  a  disposition  to  return 
to  the  use  of  chloral,  as  at  once  the  speediest  and  surest  remedy  of  the 
whole  group.  When  there  is  any  reason  to  suspect  fatty  degeneration 
of  the  heart,  however,  some  hypnotic  which  does  not  contain  chlorine 
ought  to  be  substituted  for  it,  and  paraldehyde,  hedonal  and  veronal 
have  been  introduced  in  succession  to  supply  the  need.  In  other  forms 
of  heart  disease,  chloral  may  be  used  without  danger  and  is  often  of 
great  value  as  a  hypnotic;  the  dread  of  its  aftecting  the  heart  delete- 
riously  in  ordinary  doses  is  quite  unfounded.  Chloral  is  often  prescribed 
along  with  opium,  and,  when  thus  combined,  smaller  quantities  of  each 
drug  are  required  than  would  be  necessary  if  either  were  prescribed 
alone,  and  the  sleep  following  is  very  deep  and  restful.  It  is  also  used 
very  often  to  reinforce  the  action  of  the  bromides. 

Chloral  has  been  used  externally  as  a  counter-irritant  and  anti- 
septic, but  is  more  expensive  than  many  other  equally  efficacious 
remedies.  Chloretone  solution  is  an  efficient  local  anaesthetic  on 
wounded  surfaces,  and  has  been  recommended  in  cases  of  gastric  irri- 
tation and  vomiting,  which  it  relieves  by  paralyzing  the  terminations 
of  the  sensory  nerves  in  the  mucous  membrane  of  the  stomach. 

In  cases  of  acute  Poisoning  with  chloral,  the  treatment  consists  in  the 
immediate  evacuation  of  the  stomach  by  the  stomach  tube.  Emetics 
are  of  less  value  owing  to  the  depression  of  the  medullary  centres. 
The  patient  ought  to  be  kept  warm,  and  caffeine  or  strychnine  may  be 
given  as  a  respiratory  stimulant,  while  the  complete  failure  of  the 
breathing  has  to  be  met  by  artificial  respiration.  In  acute  poisoning 
with  the  other  members  of  the  series  the  same  general  treatment  is  to 


2.T)  SUBSTANCES  ACTING  AFTER  ABSORPTION 

hv  applied.  Wlu-ii  a  i)atient  has  formed  the  habit  of  taking  one  of  these 
drugs,  it  is  goniTally  necessary  to  send  him  to  a  retreat.  It  seems 
advisable  to  witlidraw  the  drug  gradually. 

Bibliography. 
Chloral. 

Liebreich.     Das  Chloral,  ein  neues  Hypnoticum,  Berlin,  1SG8. 

Lewisson.    Arch.  f.  Anat.  u.  Phys.,  1870,  p.  346. 

Hamack  u.  Witkowski.     Arch.  f.  exp.  Path.  u.  Pharm.,  xi,  p.  1. 

V.  Merino-     Arch.  f.  exp.  Path.,  iii,  p.  185.    Zts.  f.  phys.  Chem.,  vi,  p.  480. 

Taniguli.     Virchow's  Arch.,  cxx,  p.  121. 

Remertz.     Inaug.  Diss.,  Halle,  1893.     Fortschr.  der  Mod.,  1893,  p.  20.5. 

Hamack  u.  Kleine.     Ztsch.  f.  Biol.,  xxxvii,  p.  417. 

Rohde.     Arch.  f.  exp.  Path.,  Ixix,  p.  213. 

Sulphonal. 

Kml.     Berl.  klin.  Woch.,  1888,  p.  309.    Arch.  f.  exp.  Path.,  xxxi,  p.  69. 
Kasl  u.  Weiss.     Berl.  klin.  Woch.,  1896,  p.  621. 
Vanderlinden  u.  Debuck.     Arch,  de  Pharmacodyn.,  i,  p.  431. 
Neubauer.     Arch.  f.  exp.  Path.  u.  Pharm.,  xliii,  p.  456. 
Tyson  and  Croflan.     Philad.  Med.  Journ.,  1902,  p.  882. 

Veronal. 

Fischer  and  v.  Mering.     Therap.  d.  Gegenwart,  xlv,  p.  97. 

Bachem.     Arch.  f.  exp.  Path.,  Ixiii,  p.  228. 

Grober.     Biochem.  Ztschr.,  xxxi,  p.  1. 

Jacobj  and  Roemer.     Arch.  f.  exp.  Path.,  Ixvi,  pp.  241-312. 

Amylene  Hydrate,  and  other  Soporifics. 

V.  Mering.     Therap.  Monatsh.,  1887,  p.  249. 

FHedldnder.     Ibid.,  1893,  p.  370. 

Hamack  u.  Meyer.     Ztschr.  f.  klin.  Med.,  xxiv,  p.  374. 

Cervello.     Arch.  f.  exp.  Path.,  xvi,  p.  265.      (Paraldehyde.) 

Lahousse.     Arch,  de  Pharmacodyn.,  i,  p.  209.     (Butylchloral.) 

Henriol  u.  Richet.     Arch,  de  Pharmacodyn.,  iii,  p.  191.    (Chloralose.) 

Schmiedeberg.     Arch.  f.  exp.  Path.  u.  Pharm.,  xx,  p.  203.     (Urethane.) 

Bradbury.     Croonian  Lectures,  Brit.  Med.  Jour.,  1899. 

Houghton  and  Aldrich.     Journ.  Am.  Med.  Assn.,  Sept.  23,  1899.     (Chloretone.) 

Sollmann  and  Hatcher.     Journ.  Anier.  Med.  Assn.,  Aug.  8,  1908. 


n.    OPIUM  SERIES. 

Opium  has  been  used  in  medicine  since  a  very  remote  period,  and 
although  many  substitutes  have  been  proposed  for  it  of  late  years,  it 
still  occupies  a  position  of  its  own  in  therai)eutics.  It  is  the  dried 
juice  of  the  Papaver  somniferum,  a  popi)>-  which  is  grown  chiefly  in 
India,  China,  Egypt,  Persia  and  Asia  Minor,  but  has  been  cultivated 
in  colder  climates  and  is  said  to  produce  a  more  powerful  opium  there. 
Opium  owes  its  activity  to  a  large  number  of  alkaloids,  of  which  Mor- 
'phiiic,  Codeine,  Papaverine,  Nam)ti)ir,  and  Thcbaiiic  are  the  most  im- 
portant.'   'I'lie  total  alkaloids  in  opium  vary  from  about  5-25  per  cent., 

'  Others  arc  Pscudomorphinc,  Codaminc.  Laudanine,  Laudanosino,  Meconidine, 
Lanthopini!,  Cryptopinc,  Protopinc,  Papaveramine.  Rhoeadino,  Oxynarcotine,  Narcoinc, 
Hydrocotarnini",  Gnoacopiiie  (or  racomic  Narcotinc),  and  Tritopine;  many  of  those  occur 
only  in  traces. 


OPIUM  237 

and  different  specimens  may  contain  verj'  different  quantities  of  each 
alkaloid;  for  instance,  morphine  may  vary  from  2.7-22.8  per  cent.  The 
average  percentage  of  morphine  is  10,  of  narcotine  6,  papaverine  1, 
codeine  0.5,  thebaine  0.3  and  narceine  0.2;  the  others  occur  in  too 
small  quantity  to  have  any  influence  on  the  action  of  the  crude  drug. 
The  alkaloids  are  found  in  opium  in  combination  with  meconic,  lactic, 
and  sulphuric  acids.  The  empirical  formulae  of  most  of  the  alkaloids 
have  been  determined,  those  of  the  most  important  being  morphine 
(C17H19NO3),  codeine  (CisHsiNOs),  narcotine  (C22H23NO7),  papaverine 
(C20H21NO4),  thebaine  (C19H21NO3).  Morphine,  codeine  and  thebaine 
are  derivatives  of  phenanthrene  (C14H10) ;  the  morphine  molecule  con- 
tains two  hydroxyls,  one  of  which  is  substituted  by  methoxyl  in  codeine, 
and  in  thebaine  both  are  thus  substituted  and  some  other  changes  occur 
in  the  constitution.  Narcotine,  papaverine  and  some  of  the  other 
alkaloids  are  isoquinoline  derivatives. 

The  action  of  opium  is  mainly  due  to  the  large  amount  of  morphine 
contained  in  it,  though  the  other  alkaloids  may  reinforce  its  effects. 
Morphine  acts  chiefly  on  the  central  nervous  system,  but  it  also  affects 
some  peripheral  organs,  such  as  the  intestine.  Its  action  varies  con- 
siderably in  different  animals,  and  it  is  therefore  necessary  to  con- 
sider its  effects  at  some  length  upon  the  different  classes. 

Symptoms. — In  Man  small  quantities  of  morphine  (|  gr.)  lessen  the 
voluntary  movements  and  produce  a  drowsiness  which  soon  passes  into 
sleep,  unless  the  patient  is  continually  aroused  by  his  surroundings. 
As  long  as  he  is  kept  awake,  his  actions  and  movements  show  nothing 
abnormal,  but  it  is  impossible  to  keep  his  attention  directed  to  any 
object  for  long,  and  as  soon  as  he  is  left  to  himself  for  a  few  moments 
he  sinks  into  sleep.  After  small  quantities  there  is  no  difficulty  in 
arousing  him;  in  fact,  the  sleep  seems  lighter  than  usual  and  may 
resemble  rather  a  state  of  abstraction  or  "brown  study."  In  this  con- 
dition the  imagination  is  not  depressed  to  the  same  extent  as  the  reason, 
and  it  is  often  stated,  therefore,  that  opium  at  first  stimulates  the 
intellectual  powers.  This  is  incorrect,  however — the  self-control 
and  judgment  are  lessened,  and  although  the  stream  of  thought  may 
seem  more  rapid  and  the  images  more  vivid  than  usual,  the  logical 
sequence  and  the  ideas  of  time  and  space  are  lost,  and  the  condition 
may  rather  be  compared  to  dreaming  than  to  a  real  increase  of  the 
intellectual  powers.  This  stage  of  abstraction  is  not  by  any  means 
generally  observed  and  soon  passes  into  sleep,  but  the  unchecked 
imagination  may  still  persist  in  the  form  of  dreams.  Even  in  this 
early  stage  pain  is  felt  less  acutely,  the  respiration  is  slow,  and  the 
pupil  contracted. 

In  larger  quantities  (j-|  gr.),  morphine  produces  deep,  dreamless 
sleep,  from  which  the  patient  is  still  easily  aroused,  but  which  returns 
at  once  when  he  is  left  undisturbed.  AVlien  once  aroused,  he  can  be 
kept  awake  or  can  ])e  aroused  again  after  a  short  interval  nnu-li  more 
easily,  some  time  elapsing  ai)parently  before  the  same  degree  of  depres- 
sion is  reached  again.     As  the  dose  is  increased,  the  sleep  deepens 


238  ■     SUBSTANCES  ACTING  AFTER  ABSORPTION 

into  torpor,  from  wliich  he  can  be  awakened  only  with  diffienlty,  and 
eventually  all  efforts  to  arouse  his  attention  are  fruitless  and  he  sinks 
into  coma,  which  may  be  reached  very  soon  after  a  large  dose.  During 
this  deeper  sleep  and  coma  the  respiration  is  very  slow,  the  pulse  is 
regular,  full,  and  of  moderate  speed.  The  pupils  are  contracted  to  a 
small  point  and  the  mouth  and  throat  are  dry.  The  face  is  purple 
and  congested,  and  the  skin  feels  warm,  although  the  temperature  may 
be  low.  The  breathing  generally  becomes  slower  and  weaker,  and 
occasionally  periodic  (Cheyne-Stokes).  The  cyanosis  increases,  the 
pulse  becomes  smaller  and  often  quicker,  the  pupils  remain  contracted, 
but  dilate  widely  just  before  the  final  arrest  of  the  respiration.  The 
heart  continues  to  beat  feebly  for  a  short  time  afterward. 

After  small  doses  of  morphine  the  patient  generally  awakes  refreshed, 
and,  save  for  occasional  dryness  of  the  throat  and  slight  nausea, 
apparently  quite  normal.  Not  infrequently,  however,  headache  is 
complained  of,  and  sometimes  nausea  and  vomiting,  accompanied  by 
marked  depression.  In  rare  cases  delirium,  and  even  convulsions, 
have  been-  observed  soon  after  its  injection,  but  these  symptoms  of 
excitement  are  so  rare  in  the  human  subject  as  to  be  classed  as  idio- 
syncrasies. Some  skin  affections,  such  as  itching,  and  redness,  are 
occasionally  seen  while  the  action  is  passing  off. 

The  lower  Mammals  are  much  less  susceptible  to  morphine  than  man, 
and  the  action  differs  in  the  different  species  and,  to  a  less  extent, 
among  the  individuals  of  the  same  species.  While  in  man  depression 
of  the  central  nervous  system  is  the  dominating  feature,  the  lower 
animals  often  exhibit  symptoms  of  excitation  of  some  nervous 
areas.  In  the  dog,  the  first  symptom  is  not  infrequently  vomiting  and 
defecation,  and  then  the  animal  passes  into  a  light  sleep,  from  which 
he  can  be  easily  aroused  by  touching  or  by  noise,  but  which  rapidly 
becomes  deeper,  so  that  greater  force  has  to  be  used  to  waken  him. 
When  once  awakened,  he  seems  to  sleep  less  heavily  for  a  short  time, 
and  a  much  slighter  stimulus  is  enough  to  arouse  him  if  it  is  applied 
soon  afterwards.  When  awakened  he  may  perform  apparently  \-olun- 
tary  movements  for  a  short  time,  although  more  clumsily  than  in  his 
normal  state,  but  no  complete  consciousness  is  present,  the  animal  is 
stupid  and  drowsy  and  soon  sinks  back  into  deep  slumber  again. 
The  sensation  of  pain  seems  to  be  much  lessened  but  not  entirely 
abolished,  and  reflex  movements  are  difficult  to  elicit.  After  larger 
(piantities  an  exaggerated  sensibility  to  external  stimulation  seems 
present,  for  the  animal  starts  convulsively  at  loud  sounds  and  on 
l)in(liing,  but  when  left  undisturbed  lies  in  profound  sleep.  The 
rcs])iration  is  at  first  'quick  and  dyspnauc,  the  dog  panting  as  if  after 
a  long  run,  l)ut  later  it  becomes  slow  and  labored;  the  pupil  is  nar- 
rowed; the  circulation  seems  less  affected,  although  a  congestion  of 
the  skin  and  mouth  is  often  observed.  The  rellex  irritability  may  be 
distinctly  increased  by  large  quantities,  and  before  the  respiration 
fiiiall.x-  ceases,  convulsions  generally  occur,  but  these  are  asphyxial  in 
origin  and  are  not  due  to  the  direct  action  of  the  alkaloid. 


OPIUM  239 

In  the  rabbit  and  other  rodents  the  symptoms  are  similar  to  those  seen 
in  the  dog,  but  the  depression  is  even  more  marked.  An  increase  in 
the  reflex  irritability  to  external  stimulation  is  also  evident  here,  while 
the  respiration  is  slowed  from  the  beginning.  In  the  cat  and  the  other 
felidse,  morphine  induces  wild  excitement  which  may  last  for  several 
hours,  the  animal  rushing  round  its  cage  and  appearing  unable  to  rest 
for  a  moment.  This  excitation  is  accompanied  by  a  certain  degree  of 
depression  of  the  intelligence,  however,  for  no  attempt  to  escape  is 
made  and  obstacles  are  not  avoided  so  carefully  as  by  the  normal  animal. 
After  large  doses  violent  clonic  and  tonic  convulsions  may  arise  and 
prove  fatal  from  exhaustion.  Small  quantities  of  morphine  produce 
drowsiness  in  the  horse,  ass  or  goat,  larger  quantities  restlessness  and 
excitement  which  may  pass  into  convulsions  and  death. 

In  Birds  morphine  causes  vomiting,  drowsiness,  sleep  and  stupor, 
with  slow  and  imperfect  respiration,  very  much  as  in  mammals;  in 
common  with  all  the  lower  animals  they  are  much  less  susceptible  to 
its  influence  than  man,  but  the  tolerance  does  not  seem  greater  than 
that  of  rabbits  and  dogs  when  the  drug  is  administered  hypodermically. 
It  seems  to  be  absorbed  with  difficulty  from  the  crop. 

The  Frog  is  remarkably  tolerant  of  morphine,  no  change  whatsoever 
following  the  injection  of  quantities  which  would  cause  distinct  symp- 
toms in  man.  The  first  effects  elicited  are  a  diminution  of  the  spon- 
taneous movements,  which  become  clumsy  and  ill-coordinated,  and 
finally  cease.  This  condition  may  last  for  several  hours,  when  a  series 
of  symptoms  of  an  entirely  different  nature  appear.  The  reflex  response 
to  irritation  is  distinctly  depressed  during  the  first  stage,  but  in  this 
second  phase  it  begins  to  return,  and  eventually  a  condition  of  exag- 
gerated reflex  irritability  sets  in  resembling  that  seen  in  strychnine 
poisoning,  except  that  the  frog  seems  more  easily  exhausted.  The  same 
tetanic  contractions  of  the  muscles  are  observed,  however,  with  opis- 
thotonos and  cessation  of  the  respiration,  interrupted  by  periods  of 
quiescence  and  exliaustion.  The  animal  often  dies  in  these  convulsions, 
but  it  may  survive  to  pass  again  through  a  stage  of  depression  before 
regaining  its  normal  condition. 

Action. — The  action  of  morphine  on  the  Central  Nervous  System 
in  man  is  almost  purely  depressant,  but  it  dift'ers  from  the  alcohol- 
chloroform  group  in  its  selective  action  on  the  respiration  and  on  pain 
sensation,  which  are  both  much  reduced  by  doses  which  have  little 
effect  on  the  general  consciousness.  The  pain  of  disease  is  deadened 
or  even  entirely  removed,  while  the  intelligence  is  almost  as  acute  as 
usual,  and  the  patient  is  able  to  answer  questions  and  converse  freely, 
and  may  seem  unusually  sensitive  to  impressions  caused  by  loud  noises 
or  sudden  flashes  of  light.  But  while  a  constant  pain  is  alleviated, 
a  sudden  shock  causes  almost  as  much  pain  as  without  morphine,  and 
when  the  patient  is  once  aroused,  the  sensitiveness  to  pain  apparently 
persists  for  some  time.  IMorphine  thus  seems  to  lessen  the  power  of 
attention,  and  under  it  the  individual  remains  almost  unconscious  of 
any  constant  stimulus,  but  he  can  be  aroused  by  a  sudden  intense 


240  SUBSTANCES  ACTING  AFTER  ABSORPTION 

stimulus  aud  only  relapses  to  his  former  lethargy  after  some  time. 
This  specific  action  on  pain  indicates  that  morphine  depresses  with 
special  power  the  paths  by  which  pain  stimuli  reach  the  consciousness; 
it  has  been  suggested  that  it  may  interrupt  these  paths  at  their  synapses 
in  the  region  of  the  basal  cerebral  ganglia  (Head). 

The  motor  areas  of  the  cerebral  cortex  are  not  affected  by  small  doses 
of  morphine,  but  larger  quantities  lower  and  eventually  abolish  the 
excitability  by  electric  shocks.  Exner  found  that  the  interval  between 
a  signal  and  the  movement  in  response  is  not  altered,  but  others  state 
that  the  reaction  to  a  slight  touch  is  retarded.  The  acuteness  of  sen- 
sation, as  indicated  by  the  smallest  distance  between  two  points  on 
the  skin  which  the  patient  can  recognize  as  distinct,  is  reduced  by  mor- 
phine owing  to  the  central  depression;  it  has  no  direct  action  on  the 
sensory  organs  themselves. 

While  the  effects  of  morphine  on  the  central  nervous  system  in  man 
are  chiefly  depressant,  and  this  is  especially  marked  in  pain  sensation 
and  respiration,  some  other  areas  seem  to  be  exceptionally  resistant 
to  its  action.  Thus  the  circulatory  centres  in  the  medulla  are  little 
affected  directly  by  quantities  which  depress  the  respiration  to  a 
dangerous  extent.  And  there  is,  according  to  one  view,  an  actual 
stimulation  of  the  nerve  centre  which  causes  contraction  of  the  pupil. 

In  animals,  the  central  nervous  symptoms  of  morphine  poisoning 
present  an  extraordinary  mixture  of  stimulation  and  depression  and  the 
relative  prominence  of  these  varies  widely  in  different  species.  The 
stimulation  effect  on  the  brain  is  best  manifested  in  the  wild  excitement 
of  the  cat  and  its  allies  under  morphine,  while  the  narcotic  action 
predominates  in  the  rabbit  and  to  a  less  extent  in  the  dog;  even  in  the 
cat  some  depression  of  the  intelligence  is  to  be  made  out.  In  the  cat 
and  rabbit  the  respiration  is  depressed  as  in  man,  but  in  the  dog  there  is 
a  stage  of  marked  acceleration  present  at  first.  In  the  dog  the  vomit- 
ing centre  is  excited  and  the  cardiac  inhibitory  centre  of  the  medulla 
is  also  stimulated.  It  is  impossible  at  present  to  suggest  any  general 
theory  of  the  action  of  morphine  on  the  nerve  cells  which  covers  these 
differences  in  the  behavior  of  different  animals  and  also  in  the  reaction 
of  different  nerve  centres  in  the  same  animal. 

The  effect  of  morphine  on  the  Spinal  Cord  has  been  studied  almost 
exclusively  in  the  frog.  The  reflex  irritability  in  these  animals  is 
first  diminished  to  a  slight  extent,  and  then  increased  to  the  same 
degree  as  by  strychnine.  In  Ull  animals  the  cord  is  less  depressed  than 
in  the  corresponding  stage  of  chloral  poisoning,  for  if  two  animals  are 
poisoned,  the  one  with  mori)]iine,  the  other  with  chloral,  until  no 
voluntary  movements  occur,  the  reflexes  of  the  one  poisoned  with 
m()ri)hine  are  always  found  more  active  than  those  of  the  other. 

To  sum  up  the  action  of  mor})hine  on  the  central  nervous  system,  it 
produces  great  (lc])ressi()ii  w  hicli  is  esjiecially  marked  in  the  sensation 
of  pain  and  in  the  res|)iration;  the  cerebral  motor  functions  are  less 
allcctcd  than  llic  power  of  ])ercej)tion,  the  will,  and  the  attention. 
In  man  the  faihirc  ol'  the  resi)iration  closes  the  courseof  the  intoxication, 


OPIUM  241 

but  in  the  cold-blooded  animals  a  further  development  of  excessive 
reflex  irritability  follows  which  may  pass  into  tonic  convulsions.  Even 
in  the  higher  animals  and  man  some  indication  of  this  action  on  the 
cord  may  occur,  and  in  the  feline  group  this  stimulation  involves  not 
only  the  cord,  but  also  the  motor  areas  of  the  brain. 

Respiration. — In  man  and  in  most  other  animals  the  respiration  is 
slowed  by  morphine  from  the  beginning^  (Fig.  13),  and  as  the  dose  is 
increased,  the  slowing  becomes  progressively  greater.  After  small 
quantities  the  breathing  may  be  rather  shallower,  especially  if  sleep 
follows;  but  as  the  rate  slows  the  depth  increases,  though  not  suffi- 
ciently to  compensate  for  the  slowing,  and  the  total  air  breathed  may 
fall  to  one-half  the  normal  or  less.  The  characteristic  effect  of  morphine 
is  thus  a  diminution  in  the  rhythm  of  the  centre,  which  remains  sus- 
ceptible to  reflex  stimulation,  but  is  unable  to  accelerate  the  discharge 
of  impulses  to  the  same  extent  as  normally.  The  inhalation  of  carbon 
dioxide  in  unpoisoned  animals  quickens  and  deepens  the  respiration,  but 
under  morphine,  while  it  deepens  it  as  much  as  before,  it  is  unable  to 

Fig.  13 


Respiration  of  the  cat.     At  M,  injection  of  morphine  intravenously.     The  respiration 
is  immediately  slowed  and  the  movement  is  increased  in  depth. 

quicken  it  in  the  same  measure.  If  morphine  causes  rest  and  sleep,  less 
carbon  dioxide  is  formed  in  the  tissues  and  though  less  is  excreted  owing 
to  the  slowness  of  the  breathing,  there  may  be  no  accumulation  in  the 
blood  and  the  depth  of  the  respiration  remains  unchanged  or  may  be 
shallower.  But  if  the  slowing  is  more  marked,  the  gas  accumulates  in 
the  blood  and  acting  on  the  respiratory  centre  deepens  the  breathing,  as 
it  cannot  accelerate  it  except  to  a  limited  extent. 

In  the  later  stages  of  morphine  poisoning,  the  breathing  often  becomes 
irregular,  and  this  irregularity  may  have  a  periodic  character,  a  series 
of  deep  respirations  being  followed  by  several  progressively  weaker 
ones  and  then  by  complete  inactivity  for  several  seconds.  The  breathing 
then  recommences  with  a  very  slight  movement,  followed  by  a  series 
increasing  regularly  in  strength  and  then  again  descreasing  (Fig.  14). 
This  form  of  respiration  (Cheyne-Stokes)  appears  to  arise  in  part  from 
the  depression  of  the  respiratory   centre,  in  part  from  the  asphyxia 

>  In  the  dog  there  is  often  a  preliminary  stage  of  rapid,  panting  respiration,  which 
ma^  be  secondary  to  the  emetic  action  in  this  animal. 
16 


242 


SUBSTANCES  ACTING  AFTER  ABSORPTION 


of  the  lieart,  wliich  results  from  the  inefficient  respiration  and  which 
leads  to  periodic  variations  in  the  f)lood-pressure  and  in  the  blood- 
supply  to  the  brain  (Barbour).  When  the  respiratory  centre  is  once 
aroused  l)y  the  accumulation  of  carbon  dioxide  and  by  the  anpemia,  it 
remains  less  narcotized  for  some  time  and  thus  a  series  of  respirations 
follow  which  reduce  the  carbon  dioxide  of  the  blood  and  also  relieve 
the  asphyxia  of  the  heart.  The  blood-supply  to  the  brain  increases, 
and  thus  the  stimuli  to  the  respiratory  centre  furnished  by  the  carbon 
dioxide  and  the  anaemia  are  both  removed  and  the  centre  again  becomes 
dormant  (Fig.  14)  until  asphyxia  of  the  heart  and  the  carbon  dioxide 
again  arouse  it  to  a  new  phase  of  activity. 


Fig.  14 


TraciiiRS    of    the    respiration  (upper)  and    blood-pressure  (lower)  during   Cheyne-Stokes 
respiration  in  a  eat  under  a  large  dose  of  morphine.     (Barbour.) 

Towards  the  end  the  respiration  becomes  gradually  slower  and 
weaker,  and  often  loses  its  periodic  character.  Even  after  conscious- 
ness fails  to  be  aroused  by  the  most  powerful  shocks,  some  influence 
may  be  exerted  on  the  res{)iratory  centre.  Thus  the  sudden  ajiplica- 
tion  of  cold  water  may  cause  several  deep  respirations,  although  it 
fails  to  dispel  the  stupor,  but  the  respiration  finally  fails  to  react  to 
these  applications  and  soon  afterwards  ceases. 

Jackson  has  recently  noticed  that  morphine  and  many  of  the  other 
alkaloids  of  opium  constrict  the  bronchi  in  animals;  this  aj)pears  to 
arise  from  a  direct  action  on  the  bronchial  nniscle.  It  is  not  known 
that  any  such  effect  occurs  in  man  in  morphine  ])oisoning. 

I\Iori)hine  has  little  direct  action  on  the  Circulation  in  man;  the 
heart  is  often  slightly  accelerated  at  first,  jxThaps  from  the  slight 
nausea.  In  the  dog  the  heart  is  slow  and  irregular  from  powerful 
stiiindation  of  the  vagus  centre. 


OPIUM  243 

The  blood-pressure  remains  high  and  tlie  peripheral  arteries  in 
general  show  no  change  of  calibre,  with  the  exception  of  those  of  the 
skin,  especially  of  the  head  and  neck,  which  are  dilated,  rendering  the 
face  flushed  and  hot;  as  asphyxia  comes  on  the  flush  becomes  more 
dusky  and  cyanotic,  but  the  vessels  remain  dilated,  so  that  the  face  is 
of  a  bloated,  purple  color.  The  dilatation  of  these  vessels,  which  is 
due  to  some  obscure  central  action,  has  little  influence  on  the  general 
pressure,  but  causes  a  sense  of  warmth  in  the  skin,  which  is  occasionally 
followed  by  itching  and  discomfort.  It  may  account  in  part  for  the 
increased  perspiration  often  observed,  although  this  is  doubtless  con- 
tributed to  by  other  factors.  As  asphyxia  advances,  the  pulse  may 
become  slow,  while  the  blood-pressure  varies,  either  rising  from  the 
asphyxial  activity  of  the  vasomotor  centre  or  falling  from  the  slowness 
of  the  heart.  These  effects  are  entirely  absent  if  the  blood  be  suffi- 
ciently aerated  by  artificial  respiration,  and  are,  therefore,  to  be 
regarded  as  indirect  results  of  the  action  on  the  respiratory  centre. 

The  selective  action  of  morphine  is  thus  well  illustrated  in  its  effects 
on  the  medulla  oblongata  in  man,  for  the  respiratory  centre  is  para- 
lyzed before  the  centres  for  cardiac  inhibition  and  vaso-constriction  are 
affected  to  any  marked  extent. 

The  peripheral  Muscles  and  Nerves  are  also  unaffected  by  morphine 
in  any  except  overwhelming  doses.  Even  when  directly  applied  to 
the  nerve  it  has  but  little  effect  on  the  irritability  (Waller).  It  is  often 
stated  that  the  sensory  terminations  are  paralyzed  by  morphine,  and 
solutions  are  therefore  injected  into  the  seat  of  pain,  or  liniments  are 
rubbed  into  the  skin  over  it,  but  as  a  matter  of  fact,  morphine  seems 
entirely  devoid  of  any  such  local  action.  The  sensibility  of  the  skin 
is  lowered  by  an  injection,  it  is  true,  but  no  more  so  at  the  point  of 
application  than  in  other  parts  of  the  body,  so  that  the  action  appears 
to  be  central. 

In  morphine  poisoning  in  man,  the  Pupil  is  contracted  to  pin-hole 
dimensions  until  just  before  the  final  asphyxia,  when  it  dilates  widely. 
In  some  animals,  such  as  the  dog  and  rabbit,  the  same  effects  are  seen, 
while  in  birds  the  pupil  remains  unaffected,  and  in  animals  in  which 
morphine  causes  movement  and  excitement,  it  is  dilated  widely.  The 
contraction  arises  from  direct  or  indirect  stimulation  of  the  oculomotor 
centre,  and  not  from  any  local  changes  in  the  eye,  for  when  applied 
directly  to  the  conjunctiva  morphine  has  no  effect;  atropine  applied  to 
the  conjunctiva  at  once  removes  the  mj'osis  produced  by  morphine. 
The  terminal  dilatation  seen  in  man  is  not  due  to  any  direct  action 
of  the  poison,  but  is  a  result  of  the  general  asphyxia. 

As  a  general  rule  the  Secretory  Glands  seem  to  be  rendered  less  active 
than  usual  by  morphine.  When  it  produces  nausea  it  may  increase 
the  saliva  and  the  mucus,  but  these  are  the  usual  accompaniments  of 
this  condition  and  cannot  be  considered  due  to  any  special  action  of 
the  poison.  The  sweat  glands  are  exceptions  to  the  general  rule,  how- 
ever, for  slight  perspiration  is  generally  observed  from  the  therapeutic 
action,  and  profuse  perspiration  is  seen  before  death  in  some  cases  in 


244  SUBSTANCES  ACTING  AFTER  ABSORPTION 

man  from  the  effects  of  the  asphyxia.  The  urine  does  not  generally 
show  any  distinct  alteration  after  morphine  in  man,  but  there  is  not 
infrequently  retention  in  the  bladder  because  the  sphincter  reflex  is 
absent. 

The  Alimentary  Canal  manifests  some  distinct  changes  under  mor- 
l)hine,  which  have  not  yet  been  completely  explained.  In  the  human 
subject  its  injection  is  occasionally  followed  by  some  nausea,  which  is 
much  more  frequently  present,  however,  during  recovery  from  the 
drug.  In  the  dog  nausea  and  vomiting  are  almost  invariable  sequelje 
of  its  application  in  any  form,  and  from  the  rapidity  with  which 
they  follow  its  subcutaneous  injection  would  seem  to  be  due  to 
its  acting  on  the  medullary  centre.  Small  quantities  of  opium  or 
morphine  lessen  the  sensation  of  hunger  in  the  human  subject,  but  this 
is  probably  to  be  attributed  to  central  action  rather  than  to  any  effects 
on  the  stomach.  Riegel  states  that  in  man  and  the  dog  the  gastric 
secretion  is  generally  retarded  at  first  but  is  subsequently  increased 
to  a  considerable  extent.  This  occurs  whether  the  drug  be  admin- 
istered by  the  mouth  or  hypodermically  and  is  therefore  due  to  some 
change  induced  by  it  after  absorption.  The  pancreatic  secretion  is 
lessened  by  morphine  from  direct  action  on  the  gland.  The  rate  of 
absorption  in  the  stomach  and  bowel  appears  to  be  unchanged  by 
morphine. 

The  effects  on  the  intestine  vary  with  the  species  of  animal.  In  man 
morphine  slows  the  peristalsis  and  induces  constipation,  and  in  most 
animals  small  quantities  have  this  effect;  opium  and  morphine  are  very 
extensively  used  in  therapeutics  to  quiet  the  movements  of  the  bowel. 
INIagnus  found  that  the  constipating  action  could  be  elicited  after  all  the 
nerves  to  the  stomach  and  bowel  were  divided,  so  that  it  is  quite  inde- 
pendent of  the  action  on  the  central  nervous  s^^stem.  He  states  that 
the  passage  of  food  through  the  stomach  is  much  delayed  in  the  cat 
through  a  persistent  contraction  of  the  sphincter  antri  pylorici  which 
keeps  the  contents  in  the  cardiac  end,  and  later  of  the  pyloric  sphincter 
^\'hich  delays  their  passage  into  the  duodenum.  Their  passage  through 
the  bowel  is  also  slower  than  usual,  and  this  retardation  of  the  intestinal 
peristalsis  is  especially  marked  when  it  has  been  previously  accelerated 
by  irritant  purgatives  such  as  colocynth.  This  slow  passage  of  the 
contents  along  the  canal  permits  of  more  complete  absorption  of  the 
(hiids  and  thus  leads  to  the  stools  being  fewer  and  of  firmer  consistence. 
In  addition  there  is  less  secretion  from  the  intestinal  mucous  membrane 
under  morphine.  In  man,  the  effects  of  morphine  in  the  movements 
of  the  alimentary  canal  resemble  those  in  animals  in  general  characters. 
But  the  delay  in  the  stomach  is  less  marked,  while  that  in  the  intestine 
is  greater.  The  contents  pass  through  the  small  gut  more  slowly  than 
nortnally  anri  m;ikc  a  prolonged  stay  in  the  caecum  and  lower  part 
of  the  ascending  colon,  and  this  delay  in  the  large  bowel  is  the  chief 
factor  in  the  constijjation.  The  action  in  slowing  the  gastric  movements 
is  most  marked  in  tlie  young  and  may  be  almost  unnoticeable  in  adults 
(Zehbej.    In  both  cases  the  action  is  a  peripheral  one  in  the  wall  of  the 


OPIUM  245 

stomach  and  bowel.  \'cry  large  doses  cause  violent  peristalsis  and 
repeated  evacuation  of  the  bowel  in  the  dog  and  cat,  but  this  effect 
does  not  occur  in  man  even  in  morphine  poisoning;  it  has  not  been 
satisfactorily  explained. 

]\Iorphine^  frequently  causes  a  slight  fall  in  the  Temperature,  which 
may  be  explained  by  the  less  active  movements  and  the  dilatation  of 
the  cutaneous  vessels;  sometimes  a  slight  preliminary  rise  in  the  tem- 
perature has  been  seen  in  man.  It  is  found  that  animals  under  mor- 
phine react  less  to  an  increase  in  the  surrounding  temperature  than 
unpoisoned  ones;  i.  e.,  a  normal  animal  exposed  to  a  high  temperature 
takes  measures  to  prevent  its  internal  temperature  from  rising  above 
the  normal,  while,  under  morphine,  these  measures  are  less  effective, 
and  the  temperature  rises  more  rapidly  and  to  a  greater  height;  this 
indicates  that  the  temperature  centre  in  the  brain  is  rendered  less 
sensitive. 

Metabolism. — The  excretion  of  carbonic  acid  is  lessened  during  the 
depression  stage,  while  in  those  animals  in  which  excitement  is  pro- 
duced, it  may  be  considerably  augmented  from  the  increased  muscular 
movement.  The  imperfect  respiration  leads  to  an  increase  in  the 
lactic  acid  of  the  blood  and  urine  and  to  the  disappearance  of  glycogen 
from  the  liver.    Sugar  may  appear  in  the  urine  from  the  same  cause.^ 

Excretion. — Morphine  is  excreted  mainly  by  the  digestive  tract,  in 
the  saliva,  stomach  and  bowel,  and  is  therefore  found  in  large  quan- 
tities in  the  fseces  even  after  hypodermic  injection.  Traces  of  it 
occur  also  in  the  urine  after  large  doses.  It  appears  in  the  stomach 
very  soon  after  injection;  a  weak  reaction  occurring  after  two  and  one- 
half  minutes  according  to  Alt,  but  after  about  an  hour  no  further 
excretion  into  the  stomach  has  been  shown  to  occur,  although  its  nar- 
cotic action  persists  much  longer.  A  certain  amount  of  the  morphine 
undergoes  partial  oxidation  in  the  tissues,  and  some  oxidation  products 
have  been  said  to  occur  in  the  urine. 

Tolerance. — The  continued  use  of  morphine  or  opium  leads  to  a  con- 
dition of  tolerance,  in  which  enormous  doses  of  the  drug  are  necessary 
to  elicit  any  effect.  Faust  has  succeeded  in  producing  a  similar  state 
in  dogs,  and  finds  that  much  more  morphine  is  oxidized  in  the  tissues 
in  this  condition  than  in  untreated  animals;  for  when  a  normal  dog 
received  an  injection  of  morphine,  over  60  per  cent,  of  the  amount 
injected  could  be  recovered  from  the  stools,  while  when  a  much  larger 
quantity  was  injected  into  a  tolerant  animal,  none  whatever  was  found 
in  the  excreta.  The  absence  of  symptoms  from  large  doses  in  mor- 
phinists is  not  due  wholly  to  the  poison  being  oxidized  before  it  can 
reach  the  brain,  however,  for  Cloetta  was  able  to  isolate  large  quantities 
from  the  tissues  of  animals  in  which  tolerance  had  been  established. 
And  while  tolerance  is  easily  acquired  by  some  centres,  others  fail  to 
develop  it;  thus  dogs  which  have  become  so  tolerant  that  even  large 
quantities  fail  to  induce  narcosis,  continue  to  react  to  even  small  quanti- 
ties by  slowing  of  the  pulse;  the  cerebral  nerve  cells  have  become 
tolerant,  but  those  of  the  vagus  centre  have  failed  to  do  so  (Egmond). 


240  SUBSTANCES  ACTING  AFTER  ABSORPTION 

Sonic  nerve  cells  tluis  hccome  habituated  to  the  presence  of  morphine 
in  the  i)loo(l  and  cease  to  react  to  it  as  strongly  as  in  normal  individuals, 
while  others  remain  susceptible;  in  addition,  the  tissues  acquire  a 
greater  power  of  oxidizing  mori)hine.  The  attempt  to  find  "anti- 
morphine  serum"  has  proved  fruitless. 

Codeine  given  in  moderate  quantities  resembles  morphine  in  its 
action  in  man  but  is  much  weaker.  Thus  one  grain  of  codeine  induces 
sleep  and  relieves  pain  in  about  the  same  degree  as  one-fourth  grain  of 
morphine;  the  sleep  is  said  to  be  not  so  deep  and  restful  as  that  which 
follows  the  administration  of  morphine,  and  the  patient  is  liable  to  be 
awakened  by  slight  noises,  and  is  restless  and  often  unrefreshed  when 
he  awakens.  Somewhat  larger  quantities,  instead  of  inducing  deeper 
sleep,  increase  the  restlessness  and  cause  a  considerable  exaggeration 
in  the  reflex  excitability.  The  respiration  is  slowed  in  the  same  way 
as  by  morphine  but  here  again  morphine  is  at  least  four  times  as  power- 
ful ;  large  doses  of  codeine  do  not  slow  the  respiration  further.  The 
pupil  is  slightly  contracted  during  the  codeine  sleep,  but  dilates  when  the 
excitement  stage  follows.  Codeine  thus  depresses  the  central  nervous 
system  in  man,  though  there  are  indications  of  stimulation  also  when 
large  quantities  are  used.  In  animals  these  symptoms  of  exckation 
are  more  obvious,  however,  especially  in  the  spinal  cord,  in  which  the 
reflexes  are  rendered  more  acute  and  may  finally  give  rise  to  spasms. 
In  the  cat  morphine  induces  cerebral  excitement,  but  under  codeine 
this  is  often  seen  in  the  dog  also  and  even  to  a  slight  extent  in  man. 

Codeine  acts  less  on  the  stomach  and  bowel  than  morphine,  but  when 
given  in  doses  adequate  to  cause  narcosis,  it  also  causes  constipation. 
It  is  excreted  by  the  urine  unchanged  and  none  has  been  shown  to 
undergo  destruction  in  the  tissues,  as  occurs  in  the  case  of  morphine. 
No  tolerance  is  acquired  for  codeine  even  after  long  use,  and  patients 
may  in  fact  appear  more  susceptible  to  the  drug,  a  dose  which  at  first 
gave  relief  now  causing  nausea  and  vomiting.  It  is  i)ossible  that  this 
may  indicate  a  tolerance  of  some  parts  of  the  central  nervous  system, 
which  is  not  shared  by  the  vomiting  centre. 

Codeine  is  methylmorphine,  and  a  number  of  similar  compounds  have  been 
formed  ariificiallv,  siu-h  as  ethyhnorphine  and  amylmorphine.  Two  of  these, 
ethylniorpliinc  (Dionine)  and  benzyhnorphine  (Peronine)  liave  been  introduced 
iiitcj  tli(M-ai)cutic.s,  Ijut  appear  to  i)0ssess  no  advantages  over  codeine. 

Oxydimorphine  (CadLcNiOc)  lias  been  found  in  opium  by  some  investi- 
gators, and  has  a  very  weak  narcotic  action  resembling  that  of  morphine. 

Heroine,  (Uacetyhnorphine,  is  an  artificial  alkaloid  formed  from  morphine 
by  substituting  acetyl  for  its  two  liydroxyls,  and  has  attracted  some  attention 
recently  through  its  being  advocated  as  a  respiratory  sedative  in  cough.  It 
appears  to  resemble  morphine  in  its  general  elTects,  but  acts  more  strongly  on 
the  respiration,  and  is  therefore  more  poisonous.  The  action  on  the  respiration 
is  the  same  in  kind  as  that  of  morphine  but  is  stronger,  and  the  advantages 
claimed  for  heroine  by  its  advocates  have  not  been  contirnied  by  impartial 
investigation.  It  api)ears  to  have  rather  more  depressant  etTects  on  the  cerebruin 
than  codeine.  In  animals  large  do.ses  cause  excitement  and  convulsions,  and  in 
man  these  have  also  been  observed  in  cases  of  poisoning;  the  exhaustion  from 
lliese  convulsions,  is  the  cause  of  death  in  animals.     Heroine  is  excreted  mainly 


OPIUM  247 

in  the  urine  unchanged,  hut  some  is  found  in  the  stools.  \Vh(>n  it  is  given  for 
some  time,  the  tissues  learn  to  destroy  it  and  it  no  longer  appears  in  the  excre- 
tions. A  certain  tolerance  is  observed,  for  the  narcotic  action  becomes  less 
marked  and  may  entirely  disappear,  but  the  exciting  action  of  large  doses 
remains  unaffected  (Langer).  Cases  of  heroine  habit  have  been  described 
repeatedly.  On  the  whole  the  evidence  of  experimental  and  clinical  observers 
seems  to  indicate  that  heroine  deserves  a  place  between  morphine  and  codeine. 

Papaverine  stands  midway  between  codeine  and  morphine  in  its  action  on 
the  central  nervous  system,  but  is  a  comparatively  weak  poison.  Even  in 
large  quantities  it  has  not  the  soporific  action  of  morphine,  nor  does  it  produce 
the  same  degree  of  excitement  as  codeine.  Comparatively  small  quantities 
are  followed  by  sleep,  but  this  does  not  become  deeper  as  the  dose  is  increased. 
On  the  contrary,  the  reflex  excitability  is  augmented,  and  after  very  large 
quantities  some  tetanic  spasm  may  be  elicited,  but  this  seems  to  be  of  spinal 
origin  entirely,  while  that  produced  by  codeine  points  rather  to  an  affection  of 
the  lower  part  of  the  brain.  Papaverine  has  more  tendency  to  slow  the  heart 
rhythm  than  either  morphine  or  codeine;  it  apparently  acts  directly  on  the 
heart  muscle  and  not  through  the  regulating  centres.  The  blood-pressure  is 
little  affected  by  ordinary  quantities,  however.  Papaverine  is  said  to  have  a 
greater  action  in  lessening  peristalsis  than  the  other  alkaloids. 

Narcotine  resembles  codeine  rather  than  morphine,  but  has  even  less  depres- 
sant action,  especially  in  mammals.  In  the  frog  a  short  stage  of  depression 
is  elicited,  but  this  soon  gives  place  to  strychnine-like  exaggeration  of  the 
reflex  excitability.  In  manmials  there  may  be  but  little  appearance  of  depression, 
the  injection  being  followed  by  a  condition  of  excitement  inmiediately — rest- 
lessness and  tremors  with  increased  reflexes,  which  eventually  lead  to  con- 
vulsions, during  which  the  animal  generally  succumbs  exactly  as  in  strychnine 
poisoning.  The  pulse  is  considerably  slower  after  narcotine  injection,  from  a 
direct  action  of  the  drug  on  the  heart.  The  sympathetic  ganglia  are  first  stimu- 
lated and  then  paralyzed.  Narcotine  is  a  very  much  less  poisonous  body  than 
either  morphine  or  codeine,  and  very  large  cjuantities  have  been  administered 
repeatedly  with  little  or  no  narcotic  effect.  It  is  a  compound  of  hydrocotarnine, 
another  opium  alkaloid,  with  opianic  acid.  Hydrocotarnine  apparentlj^  acts 
very  much  in  the  same  way  as  narcotine,  but  produces  even  less  depression. 

Narceine  has  little  or  no  action  of  any  kind.  It  is  exceedingly  insoluble 
in  water,  and  its  salts  are  broken  up  in  aqueous  solution,  so  that  it  is  probably 
absorbed  very  slowly  and  imperfectly. 

Thebaine  seems  to  have  practically  no  depressant  action.  It  sometimes 
produces  some  heaviness  and  confusion  in  man,  but  this  is  accompanied  by 
symptoms  exactly  resenibling  those  described  under  strychnine,  and  it  may 
therefore  be  considered  as  belonging  to  the  latter  series  rather  than  to  that 
of  morphine;  it  is  very  much  less  active  than  strychnine,  however.  Thebaine 
seems  to  differ  from  morphine  also  in  its  effects  on  the  bowel,  for  Vamossy 
finds  that  it  increases  peristalsis  instead  of  allaying  the  irritability.  Laudanine 
seems  to  resemble  thebaine  very  closely  in  its  effects. 

The  other  alkaloids  occur  in  very  minute  quantities  in  opium  and  possess 
no  great  interest  from  the  therapeutic  point  of  view.  Very  little  has  been 
done  to  elucidate  their  pharmacological  action,  but  those  which  have  been 
examined  seem  to  produce  eft'ects  resembling  those  of  the  better  known  mem- 
bers of  the  group.  In  frogs,  small  doses  of  Cryptopine  and  Protopine  produce 
a  narcotic  condition  similar  to  that  following  the  injection  of  morphine,  but 
the  reflex  irritability  does  not  show  the  same  exaggeration  afterward;  larger 
quantities  cause  complete  paralysis  of  the  whole  central  nervous  system  and 
partial  paralysis  of  the  terminations  of  the  motor  nerves,  which  gives  rise  to 
irregular  contractions  and  relaxations  of  the  muscles  when  the  nerves  are 
stimulated  (Hale).  In  mammals,  no  depression  occurs,  but  restlessness  and 
eventually  convulsions,  which  do  not  seem  to  be  of  spinal  origin  but  rather 

The  heart  is  slow  and 


248  SUBSTANCES  ACTING  AFTER  ABSORPTION 

weak,  ami  some  doprossioii  of  the  vaso-motor  centres  is  caused  by  large  quantities 
of  the  poisons.  The  respiration  does  not  seem  to  be  dejiressed,  l)ut  rather  to  be 
accelerated,  save  by  the  largest  doses.  They  ]iaralyze  the  terminations  of  the 
sensory  nerves  on  local  application  in  the  same  way  as  cocaine.  The  action  of 
these  two  alkaloids  on  the  heart  would  seem  to  be  further  developments  of 
the  heart  action  noted  after  narcotine  and  papaverine. 

In  man  morphine  is  much  the  most  dangerous  of  the  opium  alkaloids,. 
l)ecau.se  death  is  produced  in  the  narcotic  stage  through  asphyxia. 
In  most  animals,  however,  thebaine,  codeine  and  laudanine  are  more 
toxic,  because  the  failure  of  the  respiration  does  not  occur  in  the  stage 
of  depression,  but  during  the  convulsions. 

Opium  itself  contains,  besides  the  alkaloids  already  discussed,  various 
acids  with  which  they  are  in  combination,  meconic,  lactic,  and  sul- 
phuric acid,  but  none  of  these  possess  any  action  of  importance. 
Along  with  these  are  found  gums,  sugars,  albumins,  wax  and  the  other 
common  constituents  of  plant  juices,  but  these  merely  tend  to  delay 
tlie  absorption  of  the  active  constituents,  and  cannot  be  said  to  play 
any  part  in  the  effects  of  opium.  Of  the  alkaloids,  morphine  is  present 
in  greatest  abundance,  and  is  also  the  most  powerful  in  its  effects 
on  man.  According  to  most  observers  the  action  of  opium  on  the  brain 
is  practically  identical  with  that  of  morphine,  when  due  allowance 
is  made  for  the  slower  absorption  of  the  crude  drug  from  the  bowel; 
if  any  difference  exists,  it  is  so  small  as  to  be  inappreciable  in  ordinary 
cases.  But  an  old  view  that  opium  is  a  better  narcotic  than  morphine 
has  recently  been  resuscitated,  and  a  preparation  of  all  the  alkaloids  of 
opiiuu  without  the  other  constituents  has  been  introduced  under  the 
name  of  Pantopon  fomnopon).  This  has  not  been  shown  to  have  more 
narcotic  action  than  the  morphine  that  it  contains,  and  its  composition 
\aries  considerably.  According  to  Straub,  the  alleged  superiority  of 
oi)ium  over  morphine  as  a  narcotic  is  due  to  its  containing  narcotine, 
which  in  itself  has  comparatively  little  depressant  power,  but  which 
intensifies  that  of  morphine  to  a  marked  extent  when  they  are  admini.s- 
tered  together.  He  has  therefore  introduced  morphinc-narcotine  meco- 
nate  under  the  name  of  Narcophine  as  superior  to  morphine  in  narcotic 
l)ower  while  less  depressant  to  the  respiration.  The  superiority 
of  these  prei)arati()ns  as  narcotics  over  nu)ri)hine  has  not  yet  been 
<'stablish('(l,  and  their  relative  power  in  relieving  pain  is  also  unknown. 
As  regards  their  action  on  the  alimentary  tract,  opium  and  pantopon 
are  i)ractically  identical,  morphine  is  less  constipating  than  i)antopon, 
and  narcoi)liine  is  the  least  active  of  all.  The  greater  sedative  effect 
of  opium  and  j)antoi)on  on  the  intestine  may  i)robably  be  due  to  the 
])rcscncc  of  j)apaverine  (Zehbe)  and  codeine  (Hesse). 


U,  S.  P.  Phep.\r.\tions. 

Oi'icM.  the  dried  milky  exudation  obtained  by  incising  the  unripe  capsules 
of  Tapaver  .sonniiferum,  yields  when  moist  not  less  than  i)  i)er  cent,  of  crystal- 
lized morphine.     1  )o.se,  0.1  G.  (1.^  grs.). 


OPIUM  249 

Opii  Pulvis,  dried  and  powdered  opium,  yielding  12  per  cent,  of  crystal- 
lized morphine.    Dose,  0.065  G.  (1  gr.).' 

ExTRACTUM  Opii,  the  dried  aqueous  extract,  contains  20  per  cent,  of  mor- 
phine.    Dose,  0.03  G.  (|  gr.). 

TiNCTURA  Opii  (Laudanum)  contauis  10  per  cent,  of  opium,  or  from  1,2  to 
1.25  per  cent,  of  morphine.    Dose,  0.5  c.c.  (8  mins.).^ 

Pulvis  Ipecacuanha  et  Opii  (Dover's  Powder),  10  per  cent,  each  of  opium 
and  ipecacuanha  powders.    Dose,  0.5  G.  {1\  grs.). 

Pilulce  Opii,  each  containing  0.065  (1  gr.)  of  powdered  opium  or  0.008  {\  gr.) 
of  morphine.     Dose,  1  pill 

TiNCTURA  Opii  Camphorata  (Paregoric)  contains  four  parts  of  opium  per 
thousand,  along  with  benzoic  acid,  camphor,  oil  of  anise  and  glycerin.  Dose, 
8  c.c.  (2  fl.  drs.).^ 

Morphina  (C17H19NO3+H2O),  colorless  crystals  without  odor  but  with  a 
bitter  taste,  practically  insoluble  in  water  and  only  slightly  soluble  in  alcohol. 
Dose,  0.010  G.  (i  gr.) 

MORPHINiE  HyDROCHLORIDUM. 

Morphine  Sulphas. 

The  hydrochloride  and  sulphate  are  soluble  in  about  15-17  parts  of  water, 
less  so  in  alcohol.  They  form  white,  silky  crystals  with  a  bitter  taste.  Dose, 
0.015  G.  (i  gr.). 

CoDEiNA  (C18H21NO3+H2O),  white  or  nearly  transparent  crystals  with  a 
faintly  bitter  taste,  soluble  in  80  parts  of  water  and  in  1.6  parts  of  alcohol. 
Dose,  0.03  G.  Q  gr.). 

Codeine  Phosphas,  white  needle-shaped  crystals  with  a  bitter  taste,  soluble 
in  about  2  parts  of  water.    Dose,  0.03  G.  {\  gr.). 

Heroine,  or  diacetylmorphine  hydrochloride  (unofficial),  a  white  crystalline 
powder  soluble  in  3  parts  of  water.     Dose,  3-10  mgs.  {h-k  gr.). 


B,  P.  Preparations. 

Opium,  the  juice  obtained  by  incision  from  the  unripe  capsules  of  Papaver 
somniferum,  inspissated  by  spontaneous  evaporation.  When  dried  it  contains 
9|-10|  per  cent,  of  anhydrous  morphine.    Dose,  \-2  grs. 

ExTRACTUM  Opii  Siccum  contains  20  per  cent,  of  morphine.    Dose,  \-l  gr. 

TiNCTURA  Opii,  Laudanum,  contains  1  per  cent,  of  morphine,  or  about  1  gr. 
of  opium  in  10  mins.  Dose,  5-15  mins.  for  repeated  administration;  for  a 
single  administration  20-30  mins. 

TiNCTURA  Camphors  Composita,  Paregoric*  or  Paregoric  Elixir,  contains 
camphor,  benzoic  acid,  oil  of  anise  and  \  gr.  of  opium  in  each  fl.  dr.  (/,t  per 
cent,  of  morphine.    Dose,  \-l  fl.  dr. 

Pulvis  Ipecacuanha  Compositus,  Dover's  Powder,  contains  10  per  cent, 
each  of  opium  and  ipecacuanha  in  powder.    Dose,  5-15  gr. 

Pulvis  Kino  Compositus  contains  5  per  cent,  of  opium  along  with  kino 
and  cinnamon.    Dose,  5-20  grs. 

Pulvis  Greta  Aromaticus  cum  Opio  contains  2\  per  cent,  of  opium  along 
with  aromatic  chalk  powder.    Dose,  10-60  grs. 

1  Practically  identical  forms  are  Opium  deodoratum  and  Opium  granulatum,  each  con- 
taining 12  per  cent,  of  morphine.     Dose,  0.065  G.  (1  gr.). 

2  Another  10  per  cent,  tincture  is  Tinctura  Opii  Deodorati.    Dose,  0.5  c.c.  (8  mins.). 
'An   unimportant  preparation  is  Mistura  Glycyrrhizoe  Composita  (Brown   Mixture), 

formed  from  liquorice,  syrup,  acacia,  wine  of  antimony,  spirits  of  nitrous  ether  and 
camphorated  tincture  of  opium,  and  containing  only  about  1  part  of  opium  in  2000. 
Dose,  8  c.c.  (2  fl.  drs.),  _  .... 

"  Scotch  Paregoric  or  Tinctura  Opii  Ammoniata  contains  ammonia,  benzoic  acid,  oil 
of  anise  and  nearly  5  grs.  of  opium  in  the  fluid  oz.  (0.1  per  cent,  morphine).  Dose, 
4-1  fl.  dr. 


250  SUBSTANCES  ACTING  AFTER  ABSORPTION 

TiLiLA  l'i>uMBi  CUM  Opio  coiitaiiis  12  ])cr  cent,  of  opium  along  with  lead 
aix'tate.     Dose,  2-4  grs. 

PiLiLA  S.M'OMs  CoMi'OsiTA,  Contains  20  pci-  cent,  of  opium.    Dose,  2-4  grs. 
SuiM'osiTouiA  Plumbi  Composita,  each  contains  3  grs    of  lead  acetate  and 

I  gr.  of  opium.' 

MouPHiN^  Hydrochloridum  (Ci7Hi9N03,nCl,3H20),  acicular  prisms  soluble 
in  24  parts  of  cold  water,  one  part  of  boiling  water,  or  50  of  alcohol.     Dose, 

Morphincc  Tartras-  ((C,7Hi9N03)2C4H606,3H20),  a  white  powder  soluble  in 

I I  parts  of  cold  water,  insolu))le  in  alcohol.    Dose,  |-|  gr. 
Liquor  Morphine  Hydrociiloridi,  1  per  cent.,  10-60  mins. 

Injectio  Morphine  Hypodermica  contains  2§  per  cent,  of  the  tartrate. 
Dose  b}^  subcutaneous  injection,  5-10  mins. 

SuPPO-siTORiA  Morphine,'  each  contains  \  gr.  of  morphine  hydrochloride. 

CoDEiN.E  Phosphas  ((Ci7H,8(CH3)N03,H3P04)23H20),  white  crystals  with  a 
slightly  bitter  taste,  soluble  in  4  parts  of  water,  much  less  soluble  in  alcohol. 
Dose,  j-l  gr. 

Syrupus  Codeine  Phosphatis,  one  fluid  drachm  contains  I  gr.  of  codeine 
phosphate.     Dose,  ^-2  fl.  drs. 

Diamorphince  Hydrochloridum,  Heroine  or  diacetylmorphine  hydrochloride,  a 
white,  crystalline  powder  having  a  bitter  taste  and  solul)le  in  3  parts  of  water. 
Dose,  5'5-i  gr. 

Therapeutic  Uses. — Opium  is  one  of  the  most  important  and  most 
extensively  used  drugs  in  the  pliarmacopoeias  at  the  present  day  as 
in  the  past.  Of  kite  years  the  crude  drug  has  been  largely  replaced 
by  morphine,  but  the  action  is  the  same,  and  although  morphine  is 
preferable  in  most  cases,  opium  is  stiU  specially  indicated  for  certain 
purposes.  In  almost  any  disease,  conditions  which  are  favorably 
influenced  by  morphine  may  present  themselves,  and  these  conditions 
alone  can  be  discussed  here. 

Pain. — As  has  been  repeatedly  mentioned,  opium  or  morphine  has 
a  special  analgesic  action  which  is  not  shared  by  its  modern  rivals 
of  the  methane  series,  and  which  justifies  the  celebrated  dictum  of 
Sydenham  that  without  opium  few  would  be  callous  enough  to  practise 
therai)euti('s.  The  general  statement  may  suffice  that  severe  pain 
indicates  opium.  P^ven  where  the  disease  itself  is  one  which  would 
in  ordinary  circumstances  contra-indicate  it,  it  must  always  be  taken 
into  consideration  whether  the  relief  of  the  pain  and  its  attendant 
restlessness  may  not  counterbalance  the  disadvantages  of  the  narcotic. 
At  the  same  time  the  danger  of  inducing  the  craving  for  morphine 
cannot  be  forgotten,  for  the  use  of  morphine  to  subdue  pain  is  perhaps 

'  Other  preparations  of  opium  are  Pulvia  Opii  Composilus,  containing  10  per  cent,  of 
opium  along  with  pepper,  ginger,  caraway,  and  tragacanth  (dose,  5-15  grs.),  and  Pilula 
Ipecacunnhw  cum  Scilta  formed  from  Dover's  powder  and  squills  and  containing  5  per 
cent,  of  opium.     Dose,  4-8  grs. 

-  The  acetate,  Morphinw  Acelas,  resembles  the  tartrate  except  in  being  less  soluble 
and  more  readily  decomijosed. 

'  (Jther  preparations  containing  morphine  are  the  two  lozenges,  Trochiscus  Morphinw 
and  Trochiacus  Morphinm  ct  Ipecacuanha,  each  of  which  contains  75'^  gr.  of  morphine, 
while  the  latter  contains  in  addition  /o  gr.  of  ipecacuanha.  Morphine  is  too  powerful 
a  drug  to  be  dispensed  in  lozenges.  The  Tinclura  Chloroformi  et  Morphimv  Compo.silti 
(chlorodyne)  contains  one  per  cent,  of  morphine,  chloroform,  prussic  acid,  capsicum, 
cannabis  indica,  oil  of  peppermint,  and  glycerin,  and  is  superduovis.     Dose,  5-15  mins. 


OPIUM  251 

the  most  fruitful  cause  of  the  habit.  It  is  often  found  that  compara- 
tively small  ciuantities  of  opium  are  sufficient  to  remove  or  at  any  rate 
to  dull  pain,  hut  after  repeated  doses  the  quantity  has  to  be  increased 
owing  to  tolerance  being  attained.  Codeine  may  be  used  instead  of 
morphine  to  allay  pain,  but  has  to  be  given  in  at  least  four  times  as 
large  doses,  and  is  ineffective  in  severe  pain.  Some  forms  of  pain  are 
relieved  by  the  members  of  the  antipyrine  series,  but  these  are  less 
certain  and  more  limited  in  their  action  than  morphine.  On  the  other 
hand  the  antipyretics  often  relieve  pain  without  inducing  sleep,  and  in 
this  possess  a  great  advantage  over  opium  in  the  treatment  of  headache, 
neuralgia,  and  similar  conditions. 

Sleeplessness. — Opium  was  formerly  the  only  drug  used  to  induce 
sleep,  but  since  the  discovery  of  chloral  and  its  congeners,  it  is  used 
less  frequently.  These  fail  entirely  to  replace  it,  however,  where  the 
sleeplessness  is  due  to  pain,  while,  on  the  other  hand,  they  are  more 
efficacious  in  some  conditions  of  excitement.  Not  infrequently  opiurn 
and  chloral  are  prescribed  together  for  this  purpose,  and  the  combi- 
nation acts  more  efficiently  than  either  of  the  drugs  alone.  Each  is, 
of  course,  prescribed  in  considerably  smaller  amount  than  if  adminis- 
tered separately.  Opium  is  less  efficient  than  chloral  when  there  is 
apparently  an  increased  activity  of  the  motor  functions  of  the  brain, 
as  in  wild  delirium  and  mania,  and  sometimes  seems  to  increase  the 
excitement  even,  but  this  general  statement  is  subject  to  numerous 
exceptions,  and  morphine  is  still  largely  used  in  many  such  disorders. 
In  the  true  convulsive  diseases,  such  as  tetanus,  epilepsy  and  chorea, 
chloral  is  preferable.  In  certain  forms  of  motor  excitation,  especially 
in  insanity,  hyoscine  is  indicated  as  a  sedative,  and  in  cases  of  sleep- 
lessness from  anxiety  and  w^orry  potassium  bromide  is  generally  pre- 
ferred to  any  of  the  more  powerful  sedatives.  The  beneficial  effect  of 
morphine  in  many  acute  febrile  conditions  is  undeniable,  and,  as  in  the 
case  of  alcohol,  is  due  to  its  lessening  the  pain  and  discomfort  of  the 
patient  and  inducing  rest.  A  good  deal  of  difference  of  opinion  exists 
as  to  the  advisability  of  administering  opium  or  morphine  in  these 
conditions,  and  there  is  no  question  that  the  routine  treatment  of  fever 
by  narcotics  is  to  be  deprecated;  but  on  the  other  hand,  restlessness 
and  discomfort  may  in  themselves  aggravate  the  disease,  and  morphine 
is  distinctly  indicated  under  these  circumstances. 

The  preparations  chiefly  used  to  relieve  pain  and  promote  sleep  are 
the  extract,  laudanum,  opium  pill,  or  compound  soap  pill,  and  the 
morphine  salts  and  their  solutions,  including  the  hypodermic  injec- 
tion. 

In  Respiratory  Disorders  opium  and  morphine  are  largely  used  for 
their  effects  on  the  centre.  Where  it  is  desirable  to  lessen  its  irrita- 
bility, as,  for  example,  in  excessive  cough  and  dyspnoea,  opium  may 
be  indicated.  On  the  other  hand,  when  there  is  a  profuse  expectora- 
tion, the  irritability  of  the  centre  cannot  be  lowered  without  danger, 
and  opium  is  contra-indicated.  Opium  gives  relief  in  cases  of  asthma, 
but  there  is  always  danger  of  inducing  the  habit. 


252  SUBSTANCES  ACTING  AFTER.  ABSORPTION 

Opium  is  often  combined  with  expectorants  in  the  treatment  of 
congli,  and  a  number  of  suitable  preparations  are  provided  in  the 
pharmacopa'ias,  such  as  parefi;oric,  Dover's  powder  and  otlier  prepara- 
tions containing  ipecacuanha,  and  codeine  phosphate.  The  object 
of  combining  expectorants  with  opium  is  to  allay  excessive  coughing; 
the  opium  reduces  the  excitability  of  the  centre,  while  the  expectorant 
causes  a  secretion  of  mucus  in  the  respiratory  passages  and  thus  pro- 
tects the  irritated  mucous  membrane.  The  combination  is  indicated 
only  in  dry  cough  with  little  expectoration,  and  when  there  is  abundant 
sputum  to  be  removed  by  coughing  the  treatment  may  be  harmful. 
Codeine  is  often  preferred  to  morphine  in  these  cases,  because  it  reduces 
the  excitability  of  the  respiratory  centre  with  less  marked  cerebral 
depression.  Heroine  and  dionine  were  introduced  as  superior  to  codeine 
in  this  respect,  but  impartial  investigators  of  these  drugs  have  general}}' 
failed  to  obtain  better  results  from  them  than  from  codeine  and  mor- 
phine. 

In  Peritonitis  and  Intestinal  Disorders  opium  is  indicated  doubly; 
first,  for  its  general  action  in  allaying  pain  and  restlessness;  and 
secondly,  for  its  special  action  in  lessening  the  movement  of  the  intes- 
tine. Opium  is  preferable  to  morphine  for  these  purposes  because  it 
lies  longer  in  the  bowel,  and  therefore  evolves  a  stronger  action  there 
than  on  the  rest  of  the  economy,  and  also  because  the  minor  alkaloids 
have  some  constipating  effect.  In  colic,  especially  lead  colic,  it  often 
relieves  the  pain  without  increasing  the  constipation  and  seems  to  allay 
the  spasm  of  the  bowel  without  stopping  entirely  its  peristalsis.  In 
diarrhoea  opium  ma}'  be  given  to  check  the  excessive  peristalsis,  though 
in  the  severer  forms  of  dysentery  it  generally  fails  to  have  this  efi'ect, 
and  in  septic  purging  is  rather  to  be  avoided.  In  perforation  and 
hemorrhage  from  the  bowel,  opium  is  the  most  efficient  of  all  remedies, 
as  it  allows  adhesions  or  clots  to  be  formed  by  checking  movements  of 
the  intestine,  which  would  provoke  further  leakage. 

The  B.  P.  offers  a  number  of  preparations  specially  designed  for 
use  in  intestinal  disorders  and  especially  in  diarrhoea,  such  as  the  com- 
pound kino  powder,  the  compound  chalk  powder,  the  lead  and  opium 
pill,  and  the  compound  lead  suppository  and  morphine  suppository. 
Instead  of  these  the  tincture,  extract,  or  other  simple  preparation  may 
be  used. 

In  Haemorrhage,  where  the  bleeding  point  cannot  be  reached,  opium 
or  morphine  is  most  valuable.  This  is  not  from  any  direct  effect  on 
the  vessels  or  blood,  but  because  it  allays  the  restlessness  which  follows 
the  loss  of  large  quantities  of  blood  and  thus  allows  the  blood  to  clot 
in  the  ruptured  vessel.  The  same  preparations  are  suitable  here  as 
for  pain. 

In  Vomiting  morphine  is  sometimes  used  in  small  quantities,  but  it 
seems  d()ui)tful  whether  with  any  benefit. 

M()r])hine  is  not  infrequently  given  as  a  preliminary  to  general 
Anaesthesia  in  nervous  j)atients  (J  gr.),  and  in  recent  years  operations 
lia\c  often    been   performed   under  morphine  and   hyoscine   (scopola- 


OPIUM  253 

mine)  alone.  For  this  purpose  \  gr.  (10  mgs.)  of  morphine  and  about 
2^77  S^-  (0-3  mg.)  of  hyoscine  are  injected  an  hour  and  a  half  before 
the  operation,  and  again  half  an  hour  before  it.  The  anaesthesia 
induced  is  often  sufficient,  and,  if  necessary,  a  few  drops  of  ether  or 
chloroform  may  be  inhaled  to  complete  it. 

Opium  has  been  used  instead  of  quinine  in  Malaria,  and  though  it 
cannot  be  said  to  replace  the  latter,  has  a  distinct  effect  in  some  cases 
apparently.  Of  course,  symptoms  may  arise  in  malaria  as  in  other 
diseases  in  which  opium  is  specially  indicated,  but  apart  from  this, 
cases  of  malaria  of  old  standing  seem  to  be  benefited  by  opium  with 
or  without  quinine. 

Opium  or  morphine  has  sometimes  been  used  in  Diabetes  with  good 
effects;  for  though  the  glycosuria  seldom  disappears  under  its  use, 
it  is  lessened  in  some  cases  (Kaufmann).  Codeine  has  been  advised 
instead  of  morphine  in  this  disorder,  as  it  is  less  likely  to  cause  con- 
stipation and  gastric  disturbance. 

Lastly,  opium  is  used  as  a  Diaphoretic,  and  for  this  purpose  it  is 
generally  combined  with  ipecacuanha  and  prescril)ed  as  Dover's  powder. 
Although  in  itself  it  has  little  or  no  diaphoretic  action,  opium  may 
augment  the  effects  of  ipecacuanha  through  dilating  the  skin  vessels. 
Opium  and  its  alkaloids  have  no  effect  applied  to  the  skin,  and  the 
plasters,  ointments  and  other  similar  preparations  are  obsolete. 

Codeine  is  much  less  often  used  than  morphine  in  therapeutics.  It 
is  of  comparatively  little  value  in  allaying  pain  or  excitement,  but 
has  been  found  of  benefit  in  the  sleeplessness  of  melancholia.  It  is 
used  not  infrequently  as  a  sedative  in  cough,  and,  as  has  been  stated, 
in  diabetes.  There  is  little  or  no  tendency  to  form  the  codeine  habit, 
and  it  has  been  suggested  as  a  substitute  for  morphine  in  morphino- 
mania,  but  has  not  proved  efficient  in  this  condition. 

Opium  and  morphine  are  contra-indicated  in  children  at  the  breast, 
in  whom  even  minute  quantities  {e.  g.,  one  drop  of  laudanum)  may 
produce  the  most  alarming  symptoms  of  poisoning.  After  one  year 
this  special  susceptibility  seems  to  pass  off  and  the  dose  of  morphine 
has  not  to  be  reduced  more  than  that  of  other  drugs  (Dobeli).  In 
great  weakness,  especially  in  cases  where  the  respiration  is  barely 
sufficient  to  aerate  the  blood,  or  where  profuse  expectoration  is  present, 
morphine  has  to  be  administered  with  the  greatest  care.  In  cerebral 
congestion  and  meningitis  the  opiates  are  generally  contra-indicated. 
It  must  be  remembered  also  that  both  opium  and  morphine  are  liable 
to  disturb  the  digestion  and  to  cause  nausea  and  want  of  appetite, 
and  that  these  may  prevent  their  use  in  cases  in  which  they  would 
otherwise  be  suitable.  In  some  persons  opium  invariably  causes  nausea 
and  vomiting,  either  soon  after  its  administration  or  while  its  effects 
are  passing  off.  For  this  idiosyncrasy  morphine  may  be  substituted 
for  opium,  although  this  is  often  equally  nauseating,  or  chloral  and 
bromides  may  be  prescribed  with  opium  to  prevent  the  unpleasant 
after-effects.  In  all  chronic  painful  diseases  opium  or  morphine  has  to 
be  given  guardedly,  on  account  of  the  risk  of  the  formation  of  the 


254  SUBSTANCES  ACTING  AFTER  ABSORI'TION 

opium  habit;  the  patient  ought  to  be  kept  in  ignorance  of  the  drug 
used  as  far  as  possible,  and  it  should  be  alternated  with  others.  Of 
course,  in  cases  of  incurable,  hopeless  disease,  where  life  can  only  last 
a  comparatively  short  time  and  is  attended  by  severe  suffering,  this 
objection  does  not  hold,  and  it  may  be  necessary  to  administer  morphine 
without  stint  and  in  ever-increasing  quantity. 

Mt)rphinc  and  opium  are  often  said  to  be  contra-indicated  in  Bright's 
disease  of  the  kidney.  This  seems  to  be  due  to  the  belief  that  mor- 
phine is  excreted  in  the  urine,  which  has  now  been  shown  to  be  erro- 
neous. There  seems  no  reason  to  believe  that  morphine  is  harmful 
in  these  conditions,  and  in  some  forms  of  uraemia  it  has  even  been  of 
consi<lcrable  benefit. 

Acute  Poisoning  with  morphine  or  opium  is  one  of  the  commonest 
forms  of  intoxication,  with  the  exception  of  the  alcoholic.  It  is  often 
difficult  to  diagnose  from  other  forms  of  unconsciousness,  but  the 
extreme  contraction  of  the  pupils  gives  a  clue,  as  a  general  rule, 
and  if  opium  has  been  used,  the  breath  often  has  the  charac'teristic 
odor. 

The  treatment  of  acute  morphine  or  opium  poisoning  should  consist 
in  removing  the  poison  from  the  body  and  in  guarding  against  failure 
of  the  respiration. 

The  first  object  is  best  attained  by  washing  out  the  stomach  with 
the  stomach  tube,  as  emetics  generally  fail  when  morphine  has  been 
absorbed  owing  to  the  depression  of  the  centre.  Even  when  morphine 
has  been  injected  hypodermically,  gastric  lavage  may  have  some  value 
as  some  of  the  poison  is  excreted  into  the  stomach.  Water  should  be 
used  to  wash  out  the  stomach;  dilute  potassium  permanganate  solution 
has  been  advised,  but  tends  to  oxidize  the  gastric  mucous  membrane 
rather  than  the  morphine.  A  sharp  purge  may  be  given  to  remove  the 
mor})hine  excreted  into  the  bowel  and  also  to  promote  excretion  by 
irritating  the  mucous  membrane. 

In  morphine  poisoning  the  danger  is  failure  of  the  respiratory  centre. 
'J'his  may  be  combated  by  the  use  of  respiratory  stimulants  of  which  the 
best  is  caffeine  (often  given  in  the  form  of  hot  coffee).  Strychnine  has 
also  an  antagonistic  action  to  morphine  and  may  be  injected.  And 
atropine  has  been  used  to  increase  the  excitability  and  apjH'ars  to  be  of 
value  in  small  quantities;  but  not  more  than  fV  grain  should  be  used 
as  larger  amounts  tend  to  weaken  the  respiration.  Caffeine  is  safer 
and  is  at  least  as  efficacious  in  arousing  the  depressed  centre. 

liesides  increasing  the  excitability  of  the  centre  by  these  drugs,  the 
normal  stimulus  ma\'  l)e  augmented.  Thus  respiration  may  be  aroused 
rellexly  from  the  skin  by  dashing  cold  water  on  it,  or  by  irritating  it 
with  the  electric  current,  or  by  fiicking  it  with  wet  cloths.  But  the  chief 
Udrnial  stimulus  of  the  respiratory  centre  is  the  carbonic  acid  of  the 
blood,  and  an  attempt  should  be  made  to  increase  this  and  thus  to  pro- 
iiKtte  the  acTation.  This  may  be  attained  by  keeping  the  i)atient  in 
motion  as  far  as  is  possible,  in  order  that  the  nuiscles  ma\'  sui)ply  (X)^, 
l)Ut  as  this  may  have  to  be  ilone  for  several  hours,  it  entails  great  fatigue 


OPIUM  255 

both  for  patient  and  attendant.  A  more  rational  method  of  enricliing 
the  blood  with  CO2  would  be  to  allow  the  patient  to  breathe  air  con- 
taining 7-10  per  cent,  of  the  gas,  which  might  be  kept  in  readiness  in 
the  hospitals  where  opium  poisoning  is  often  encountered. 

Finally,  if  the  respiration  fails  in  spite  of  these  measures,  artificial 
respiration  must  be  employed  and  continued  as  long  as  the  heart  beats. 
Cases  of  recovery  from  enormous  doses  of  morphine  are  recorded  in 
which  artificial  respiration  was  maintained  for  many  hours. 

Chronic  Opium  or  Morphine  Poisoning  is  a  not  infrequent  condition, 
and,  unfortunately,  seems  to  be  increasing  rapidly.  Among  Eastern 
nations,  especially  in  China  and  India,  opium  is  smoked,  and  some  of 
the  morphine  is  carried  over  in  the  smoke  and  absorbed  from  the 
respiratory  tract.  This  habit  is  rare  in  European  peoples,  among 
whom  the  drug  is  taken  by  the  mouth,  generally  in  the  form  or  lauda- 
num or  of  pills,  or  is  injected  hypodermically  as  morphine  hydro- 
chloride or  sulphate.  Of  the  three  methods  the  first  seems  to  be  the 
least  harmful,  for  in  some  parts  of  China  the  majority  of  the  adult 
population  seems  to  indulge  in  it  without  the  serious  results  which  are 
met  with  in  the  Western  opium-eaters  and  morphinomaniacs.  This 
result  may  be  due  in  part  to  race,  or  to  the  fact  that  the  opium-smoker 
never  attains  to  the  immense  doses  taken  daily  in  the  cases  of  the  haJDit 
met  with  in  Europe  and  America.  In  the  beginning  the  quantity 
used  is  small,  but  as  tolerance  is  attained,  ever  larger  quantities  are 
required  to  produce  any  effect,  until,  as  De  Quincy  states  in  his 
"Confessions  of  an  Opium-eater,"  320  grains  of  opium  may  be 
required  to  stay  the  craving.  The  effects  are  generally  described  as 
stimulant,  but  it  seems  possible  that  they  consist  rather  in  depression 
of  the  sensibility,  by  which  the  unfortunate  patient  becomes  uncon- 
scious of  the  miseries  of  his  condition,  and  may  accordingly  be  able  to 
perform  his  duties  and  maintain  appearances  better  than  when  de- 
prived of  the  poison.  The  symptoms  of  the  opium  habit  are  exceed- 
ingly indefinite,  and  the  diagnosis  is  often  almost  impossible.  The 
statements  of  the  patient  ought  not  to  be  taken  into  consideration, 
because  these  unfortunates  seem  to  have  lost  all  idea  of  honor  and  >  , 
truthfulness.  As  a  general  rule  they  are  nervous,  weak  in  character  ^^'^ 
and  wanting  in  energy,  and  utterly  unfit  for  work  unless  when  sup- 
plied with  the  drug.  The  pupils  are  often  contracted,  the  heart  some- 
times irregular,  and  tremors  and  unsteadiness  in  walking  may  be 
apparent.  The  appetite  is  bad  and  a  considerable  loss  in  weight  occurs, 
and  the  movements  of  the  bowels  are  irregular,  constipation  alternating 
with  diarrhoea.  Eventually  melancholia  and  dementia  may  follow 
the  prolonged  use  of  opium,  and  especially  of  morphine.  Some  continue 
the  habit  for  many  years,  however,  and  it  would  seem  with  comparative 
immunity.  If  morphine  is  injected  habitually,  evidence  may  be  ob- 
tained from  the  small  needle  marks  on  the  front  of  the  body,  which  often 
give  rise  to  multiple  abscesses  of  small  size  from  carelessness  in  the 
disinfection  of  the  syringe.  When  other  evidence  fails,  it  may  be  neces- 
sary to  give  a  moderate  dose  disguised  in  some  unusual  way  and  to 


250  SUBSTANCES  ACTING  AFTER  ABSORPTION 

observe  if  it  induces  sleep;  in  habitual  users  the  ordinary  dose  will  have 
little  or  no  effect. 

The  treatment  of  chronic  morphine  poisoning  is  not  very  promising. 
The  will  and  self-control  would  seem  completely  paralyzed  in  many 
cases,  and  although  the  patient  wishes  to  be  freed  from  his  enemy,  he 
seems  utterly  unable  to  withstand  the  craving.  The  only  means  of 
treatment  which  promises  success  in  most  cases  is  the  strict  regime  of 
an  asylum  or  retreat,  where  the  patient  is  kept  under  constant  super- 
vision. The  immediate  removal  of  the  drug  often  produces  such 
intense  misery  and  depression  as  to  seem  actually  dangerous;  but  the 
withdrawal  ought  not  to  be  too  gradual,  and  ought  to  be  complete 
after  two  or  three  weeks  at  the  most.  The  patient  has  to  be  watched 
carefully  for  long*  after  he  has  apparently  recovered,  as  relapses  are 
exceedingly  common. 

The  morphine  habit  has  often  been  combated  by  the  substitution  of 
other  drugs,  such  as  cocaine,  but  the  result  generally  has  been  that  a 
new  and  even  more  dangerous  habit  has  been  substituted  for,  or  often 
merely  grafted  on,  the  original.  Numerous  drugs  have  been  proposed 
for  the  cure  of  morphinomania,  but  none  of  them  seems  to  have  the 
slightest  effect. 

Bibliography. 

The  literature  of  opium  is  so  immense  that  only  a  few  of  the  more  important  phar- 
macological papers  can  be  mentioned  here. 

CI.  Bernard.     Legons  sur  les  Anaesthesiques  et  sur  I'asphyxie.     Paris,  1875. 

Gscheidlen.     Untersuchungen  aus  dem  phys.  Lab.  zu  W^urzburg,  ii,  p.  I. 

Filehne.     Arch.  f.  exp.  Path.,  x,  p.  442;    xi,  p.  45.    Pfiiigcr's  Arch.,  Ixii,  p.  20L 

Loewy.     Pflliger's  Archiv,  xlvii,  p.  COL 

V.  Sckroeder.     Arch.  f.  exp.  Path.  u.  Pharm.,  xvii,  p.  96. 

Witkowski.     Arch.  f.  exp.  Path.  u.  Pharm.,  vii,  p.  247. 

Pohl.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxiv,  p.  87. 

All.     Berl.  klin.  Woeh.,  1889,  p.  560. 

Stockman  and  Dolt.  Proc.  Roy.  Soc.  Edinburgh,  1890.  British  Medical  Journal, 
1890,  ii,  p.  189,  and  1891,  i,  p.  157. 

Engel.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxvii,  p.  419.     (Protopine.) 

Rheiner.     Therap.  Monatsch.,  1889,  p.  393.    (Codeine.) 

Dreser.     Ibid.,  1898,  p.  509. 

Stursberg.     Arch,  de  Pharmacodyn.,  iv,  p.  325. 

Winlernitz.     Pflliger's  Arch.,  Ixxx,  p.  344. 

Riegel.     Ztschr.  f.  klin.  Med.,  xl,  p.  347. 

Holsli.     Ibid.,  xlix,  p.  1. 

Bashford.     Arch,  internat.  de  Pharmacodyn.,  viii,  p.  311. 

Faust.     Arch.  f.  exp.  Path.  u.  Pharm.,  xliv,  p.  217. 

Cloetla.     Ibid,  1,  p.  453. 

Bouma.     Ibid.,  1,  p.  353.    (Codeine.) 

Rilbsamen.     Ibid.,  lix,  p.  227. 

Golllieb  and  Ecckhout.     Ibid.,  Schmiedeberg-Festschr.,  p.  235. 

Magnus.  Ergebnisse  d.  Physiol.,  i,  2,  p.  437  (Respiration);  ii,  2,  p.  657  (Intestinal 
Action).     Pfiiiger's  Arch.,  cxv,  p.  316;    exxii,  p.  251;    exxxix,  p.  318  (Padtberg). 

Hale.     Amer.  Journ.  of  Phys.,  xxiii,  pp.  389,  408. 

Kanfmann.     Ztschr.  f.  klin.  Med.,  xlviii,  p.  260. 

V.  Egmond.     Arch.  f.  exp.  Path.  u.  Pharm.,  Ixv,  p.  197. 

Dfihcli.     Monatshiftc  f.  Kinderheilkundf,  ix,  No.  8. 

Slraub.      Riochcni.  ZLschr.,  xli,  p.  419;    xlii,  p.  316. 

Cu.shnu.     Journ.  of  Pharmacol,  and  Exp.  Ther.,  iv,  p.  363. 


OPIUM  257 

hanger.     Biochom.  Ztsclir.,  xlv,  p.  221. 

Zehhe.     Therap.  Monatsh.,  1913,  p.  406. 

Hesse  u.  Neukirch.     Arch.  f.  d.  ges.  Physiol.,  cU,  p.  309. 

Jackson.     Journ.  of  Pharmacol,  and  Exp.  Ther.,  vi,  p.  57. 

Minor  Drugs  of  the  Opium  Series. 

In  some  other  members  of  the  poppy  family  (Papaveraceis) ,  alkaloids  are 
found  which  bear  a  close  resemblance  to  those  of  opium.  These  are  Cheli- 
donine,  «-,  ft-  and  y-Homochelidonine,  Chelenjthrme  and  Sanguinarine:  Proto- 
pine  is  also  found  in  a  number  of  other  papaveracese.  These  alkaloids  are 
met  with  in  very  small  quantities  in  various  plants,  of  which  Sanguinaria 
Canadensis  (Bloodroot)  and  Chehdonium  majus  (Celandine)  are  the  best 
known. 

Chelidonine  and  a-homochelidonine  resemble  morphine  in  their  effects  on 
the  central  nervous  system,  but  have  even  less  stimulant  effect.  In  the  frog  no 
secondary  increase  in  the  reflex  irritability  is  produced,  but  in  some  mammals 
a  slight  stimulation  of  the  spinal  cord  may  be  caused.  They  have  the  same 
effect  as  protopine  and  cryptopine  on  the  nerve-ends  and  heart,  and  like  them 
produce  insensibility  of  the  skin  and  cornea  when  applied  locally,  through 
paralyzing  the  terminations  of  the  sensory  nerves.  The  heart  is  slowed,  partly 
owing  to  stimulation  of  the  inhibitory  centre  in  the  medulla,  and  partly  through 
direct  action  on  the  cardiac  muscle. 

Sanguinarine  has  very  little  depressant  action,  but  causes  tetanus  and  wild 
excitement,  so  that  as  far  as  its  action  on  the  central  nervous  system  is  con- 
cerned, it  deserves  a  place  between  codeine  and  thebaine  of  the  morphine 
series.  It  possesses  the  same  peripheral  action  as  protopine,  however,  and 
the  heart  is  slowed  through  direct  affection  of  the  muscle.  Sanguinarine  para- 
lyzes the  peripheral  sensory  endings  when  applied  locally,  but  this  paralysis 
is  preceded  by  a  stage  of  irritation.  It  causes  violent  peristalsis  of  the  bowel, 
and  increases  the  secretion  of  saliva.  _ 

ft-homochelidonine  resembles  protopine  and  cryptopine  closely  in  its  effects, 
causing  the  same  stimulation  of  the  lower  parts  of  the  brain  with  very  slight 
effects  on  the  intellectual  powers,  slowing  the  heart  through  its  muscular  action 
and  paralyzing  the  sensory  terminations.  .    . 

Chelerythrine  paralyzes  the  central  nervous  system  without  any  preliminary 
increase  in  the  reflex  irritability,  possesses  the  peripheral  action  of  protopine 
and  cryptopine,  and  first  irritates,  and  then  paralyzes  the  sensory  terminations. 
None  of  these  alkaloids  have  been  used  in  therapeutics,  and  there  would 
seem  to  be  no  indication  for  them  that  is  not  as  well  met  by  opium  or  morphine. 
None  of  the  plants  containing  them  have  been  used  to  any  great  extent,  although 
Sanguinaria  Canadensis  was  formerly  occasionally  prescribed  as  a  nauseating 
expectorant  and  emetic. 

Anhalonium.— A  number  of  alkaloids,  some  resembling  morphine,  others 
like  strychnine  in  their  effects  on  animals,  have  been  isolated  from  dif- 
ferent members  of  the  Anhalonium  genus  (Fam.  Cactaceaj).  In  Mexico,  and 
along  the  southern  boundary  of  the  United  States,  where  those  plants  are 
indigenous,  some  of  them  are  used  as  narcotics  in  the  religious  rites  of  the 
Indians  and  are  known  as  Pellote,  Peyotl,  or  Muscale  or  Mezcal  Buttons. 
The  symptoms  arise  for  the  most  part  from  the  cerebrum  and  differ  from  those 
of  opium  and  cannabis  indica  in  the  frequency  with  which  color  visions  are 
induced,  these  consisting  in  constantly  shifting  flashes  of  brilliant  tints.  Mezcal 
eating  does  not  induce  merriment  like  cannabis  nor  sleep  like  niorphine  but 
depression  of  some  functions  is  indicated  by  the  imperfect  coordination  of  the 
movements,  the  retarded  perception,  and  the  errors  in  the  estimation  of  time. 
The  exaltation  seems  to  be  caused  for  the  most  part  by  one  of  the  alkaloids, 
mezcaline.  Very  large  doses  have  induced  unpleasant  symptoms  through 
depression  of  the  respiration.  Anhalonium  and  pellotine,  one  of  its  alkaloids, 
have  been  used  as  narcotics  in  a  few  cases  of  insomnia. 
17 


258  SUBSTAM'E.S  ACTING  AFTER  ABSORPTION 


Bibliography. 

H.  Meyer.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxix,  p.  397. 

Schmidt.     Arch,  der  Pharmacie,  ccxxxix,  p.  393. 

Levein.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxiv,  p.  401;    xxxiv,  p.  374. 

Heffter.     Ibid.,  xxxiv,  p.  65:   xl,  p.  38.5. 

Mogilewa.     Ibid.,  xlix,  p.  137. 

Prentiss  and  Morgan.     Med.  Record,  August  22,  1896. 

Dixon.     Journ.  of  Physiol.,  xxv,  p.  69. 


m.     CANNABIS  INDICA. 

The  hemp  plant  possesses  no  pharmacological  interest  when  grown 
in  temperate  regions,  but  when  cultivated  in  warm  climates  as  in 
India,  Egypt  or  the  southern  United  States,  it  develops  products 
which  induce  marked  derangement  of  the  central  nervous  system. 
The  Indian  plant  was  formerly  supposed  to  be  a  distinct  species,  but 
differs  so  little  from  the  European  form  that  botanists  now  consider 
them  merely  varieties.  The  old  name  of  Cannabis  Indica  has,  how- 
ever, been  retained  in  medicine.  Its  introduction  into  Western  medi- 
cine dates  only  from  the  beginning  of  last  century,  but  it  has  been 
used  as  an  intoxicant  in  Asiatic  countries  and  in  Africa  since  unknown 
time,  and  under  the  names  of  Hashish,  Bhang,  Ganja,  Charas  or 
Churrus,  is  habitually  indulged  in  by  some  one  or  two  hundred  mil- 
lions of  mankind.  Some  of  the  preparations  are  smoked  either  alone 
or  mixed  with  tobacco;  others  form  an  intoxicating  drink,  while  in 
others  it  is  mixed  with  sugar  or  honey  and  taken  as  a  confection. 

The  active  principle  of  Indian  hemp  has  been  found  by  Wood,  Spivcy  and 
I']asterfield  to  be  a  red  oil  or  resin  boiling  at  a  high  temperature,  which  they 
term  Cannnhinol;  this  was  found  by  Marshall  to  induce  the  typical  effects  of 
cannabis  indica  in  man  and  animals.  Frankel  states  that  cannabinol  is  a  phe- 
nolaldchydc  of  the  formula  OH.C.oHmCOH. 

Symptoms. — The  effects  of  cannabis  indica  are  chiefly  due  to  the 
changes  in  the  central  nervous  system,  in  which  it  induces  a  mixture 
of  depression  and  stimulation  similar  to  that  seen  occasionally  under 
mori)liine.  Its  action  is  much  less  constant,  however,  and  seems  to 
depend  very  largely  on  the  disposition  and  intellectual  activity  of  the 
individual.  The  preparations  used  also  vary  considerably  in  strength, 
and  the  activity  of  even  the  crude  drug  seems  to  depend  very  largely 
on  the  climate  and  season  in  which  it  is  grown,  so  that  great  discrep- 
ancies occur  in  the  accounts  of  its  effects.  Soon  after  its  administra- 
tion, the  j)atient  passes  into  a  dreamy,  semi-conscious  state,  in  which  the 
judgment  seems  to  be  lost,  wliile  the  imagination  is  untramnieled  by 
its  usnal  restraints.  Tlie  dreams  assume  the  vividness  of  visions,  are 
of  bonndlcss  extra^•agan('e,  and, of  course,  vary  with  the  character  and 
|)nrsnits  of  the  iiidi\idu;d.  In  tlic  eastern  races  they  seem  generally 
((»  partake  of  an  amorous  nature.  The  true  believer  sees  the  gardens 
of  paradise  and    lin<ls  himself  surrounded   by   troops  of  houris  of  un- 


CANNABIS  INDICA  259 

speakable  l)eaiity,  while  the  less  imaginative  European  finds  himself 
unaccountably  happy  and  feels  constrained  to  active  movement,  often 
of  a  purposeless  and  even  absurd  character.  Ideas  flash  through  the 
"mind  without  apparent  continuity,  and  all  measurement  of  time  and 
space  is  lost.  True  halluncihations  may  appear,  but  are  often  absent, 
the  chief  features  of  the  action  being  merriment,  comfort,  well-being, 
and  self-satisfaction.  Often  less  pleasant  thoughts  obtrude  themselves, 
however,  such  as  the  fear  of  impending  death  or  of  some  imminent, 
indefinite  danger.  During  this  period  the  consciousness  is  not  entirely 
lost,  for  the  patient  often  feels  that  his  dreams  are  unreal,  his  satis- 
faction unfounded  and  his  movements  ridiculous,  but  he  cannot  restrain 
them;  he  can  give  a  coherent  account  of  his  condition  when  aroused 
and  answers  questions  intelligently.  The  sensation  of  pain  is  lessened 
or  entirely  absent,  and  the  sense  of  touch  is  less  acute  than  normally. 
Later  the'  dreams  alternate  with  periods  of  complete  unconsciousness, 
from  which  the  patient  can  be  aroused  easily,  and  the  symptoms 
eventually  pass  into  tranquil  sleep,  from  which  he  awakens  refreshed, 
and,  as  a  rule,  without  any  feeling  of  depression  or  nausea.  In  the 
majority  of  cases  the  preliminary  stage  of  exaltation  is  very  short  or 
entirely  absent  in  Europeans,  the  first  effects  of  the  drug  often  being 
heaviness,  drowsiness,  noises  in  the  ears  and  numbness  of  the  extrem- 
ities, which  pass  into  deep  sleep.  According  to  Dixon,  the  drug  is 
much  more  exhilarating  when  inhaled  than  when  swallowed,  and  this 
may  account  for  some  of  the  variations  in  its  action.  In  some  cases, 
acute  mania  and  convulsive  attacks  have  been  developed,  and  among 
the  natives  of  India  catalepsy  occasionally  occurs. 

In  animals  the  efi'ects  of  cannabis  indica  seem  to  resemble  those  in 
man  and  present  the  same  marked  variations;  a  stage  of  exaltation 
with  increased  movement  is  sometimes  present  and  is  followed  by 
depression,  lassitude,  and  sleep.  The  reflex  excitability  is  first  increased 
and  then  diminished  in  frogs.  Vomiting  is  often  induced  in  dogs  and 
cats,  but  cannabis  indica  difi^ers  from  opium  in  producing  no  disturb- 
ance of  the  digestion  and  no  constipation.  The  heart  is  generally 
accelerated  in  man  when  the  drug  is  inhaled ;  the  intravenous  injection 
in  animals  slows  the  pulse  partly  through  inhibitory  stimulation  and 
partly  through  direct  action  on  the  heart  muscle.  This  action  on  the 
heart  is  stated  by  Dixon  to  be  the  cause  of  death  after  poisonous 
quantities,  for  he  found  the  respiration  persist  for  some  seconds  after 
standstill  of  the  heart.  The  pupil  is  generally  somewhat  dilated. 
Polyuria  is  stated  to  occur  in  dogs,  in  which  cannabinol  appears  to  be 
excreted  by  the  kidneys  in  combination  with  glycuronic  acid  (P>ankel). 
Death  from  acute  poisoning  is  extremely  rare,  and  recovery  has 
occurred  after  enormous  doses.  The  continued  abuse  of  hashish  in  the 
East  sometimes  leads  to  mania  and  dementia,  but  does  not  cause  the 
same  disturl)ance  of  nutrition  as  opium,  and  the  habitual  use  of  small 
quantities,  which  is  almost  universal  in  some  Eastern  peoples,  does  not 
seem  detrimental  to  them,  although  among  Euroi)eans  it  might  possibly 
be  as  fatal  as  that  of  morphine.    Some  tolerance  is  rapidly  acquired. 


2G0  SUBSTANCES  ACTING  AFTER  ABSORPTION 


Preparations. 

Cannabis  Indica  (U.  S.  P.,  B.  P.),  Indian  hemp,  the  flowering  tops  of  the 
female  plant  of  Cannabis  sativa  (hemp),  grown  in  the  East  Indies. 

Extractum  Cannabis  Indicce  (U.  S.  P.,  B.  P.),  0.01  G.  Q;  gr.);  B.  P.,  \-\  gr. 

TiNCTURA  Cannabis  Indict  (U.  S.  P.,  B.  P.),  0.6  c.c.  (10  mins.);  B.  P., 
5-15  mins. 

The  preparations  vary  extremely  in  strength  and  many  are  entirely  inert, 
especially  when  they  have  been  kept  some  time.  Phj'-siologically  tested  prep- 
arations are  provided  by  many  firms. 

Therapeutic  Uses. — Cannabis  indica  is  used  as  a  hypnotic  in  cases  of 
sleeplessness  from  nervous  exhaustion  and,  less  often,  from  pain.  It 
is  not  nearly  so  reliable  as  opium,  and  in  fact  produces  sleep  in  only 
about  50  per  cent,  of  the  cases,  according  to  some  authors.  On  the 
other  hand,  it  does  not  disturb  the  digestion  and  produces  no  subse- 
quent nausea  and  depression,  and  may  therefore  be  employed  in  some 
cases  in  which  opium  is  contra-indicated.  It  is  of  use  in  some  cases  of 
migraine,  and  has  been  prescribed  as  a  substitute  for  opium  in  mental 
diseases. 

Bibliography. 

Marshall.     Lancet,  1897,  i,  p.  235.    American  Medical  Journal,  189S,  ii,  p.  882. 

Dixon.     Brit.  Med.  Jour.,  1899,  ii,  p.  136. 

Frankel.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlix,  p.  266. 


IV.    BROMIDES. 

It  was  formerly  widely  believed  that  the  bromides  had  no  further 
action  than  the  chlorides,  and  that  any  effects  observed  from  potas- 
sium bromide  were  due  to  the  potassium  ion,  the  bromide  ion  being 
iudift'erent.  There  is  now  no  question,  however,  that  the  bromides 
have  distinctive  effects,  for  all  bromides  induce  changes  in  the  central 
nervous  system,  which  are  not  elicited  by  the  chlorides.  The  bromide 
of  potassium  is  the  salt  most  generally  used. 

Symptoms. — The  local  action  on  the  alimentary  tract  is  the  same  as 
that  of  sodium  chloride  and  other  salts;  the  bromides  have  a  bitter 
salt  taste  and  induce  salivation  and  thirst,  and  in  large  quantities 
irritation  of  the  stomach,  nausea,  and  vomiting.  Ocasionally  diarrha^i 
has  been  observed  from  concentrated  solutions  reaching  the  intestine. 

General  Symptoms. — Ai)art  from  these  results  of  local  irritation,  the 
first  syiiiptoin  is  often  a  dull,  heavy  headache,  with  a  feeling  of  lassi- 
tude, fatigue,  disinclination  for  exertion,  mental  or  physical,  and  often 
muscular  weakness.  Thought  is  slow  and  confused,  the  memory  is 
indistinct,  ideas  are  ])ut  into  words  with  difliculty  and  the  speech  is 
ac-cordiiigly  slow  and  hesitating.  External  objects  and  movements 
arc  piTccived,  but  arouse  no  interest  in  tiie  patient,  and  ^■ery  often 
this  state  of  iipathy  i)asses  into  drowsiness  and  sleep.  The  bromides, 
however,  have  not  the  sleep-compelling  power  of  morphine  or  chloral, 
and  the  sleep  is  never  very  deej)  and  is  not  refreshing,  the  patient 


BROMIDES  261 

sometimes  feeling  dull  and  unfit  for  exertion  after  it,  and  some 
mental  confusion  often  persisting  for  several  hours  after  waking. 
The  reflexes  are  much  depressed  by  large  doses  of  Ijromido,  so  that 
touching  the  back  of  the  throat  does  not  induce  nausea,  although  the 
sensation  of  touch  may  persist.  The  mucous  membranes  of  the 
genito-urinary  tract  are  also  less  sensitive,  or  rather  their  irritation 
is  less  liable  to  set  up  reflex  movements.  After  very  large  doses  of 
the  bromides  the  conjunctiva  may  sometimes  be  touched  without 
causing  winking,  and  lessened  sensation  in  the  skin  has  been  noted 
in  some  cases.  The  pulse  and  respiration  are  slower  than  usual  after 
large  doses,  but  scarcely  more  so  than  in  sleep.  An  increase  in  the 
urine  is  often  observed. 

Acute  fatal  poisoning  with  bromides  has  seldom  or  never  occurred 
in  man,  but  after  enormous  doses  prolonged  sleep  or  stupor  has  been 
seen,  and  confusion  and  apathy  lasting  for  several  days. 

When  bromide  is  given  repeatedly  in  large  doses,  a  series  of  symp- 
toms is  often  induced  to  which  the  name  of  Bromism  has  been  applied. 
It  occurs  much  more  rapidly  in  some  persons  than  in  others,  and  may 
suddenly  appear  after  the  patient  has  been  taking  the  drug  for  months 
without  any  untoward  results.  The  commonest  symptoms  of  bromism 
are  skin  eruptions  of  various  kinds,  very  often  commencing  as  acne 
of  the  face.  In  severe  cases  the  pustules  of  acne  may  coalesce  and 
form  small  abscesses,  which  are  followed  by  ulcers.  In  other  cases 
the  skin  affection  partakes  rather  of  the  nature  of  a  localized  blush  or 
erythema  and  sometimes  copper-colored  blotches  have  been  observed. 
Some  disturbance  of  the  digestio7i  and  loss  of  appetite  is  often  met 
with  from  the  local  action  of  large  quantities  of  the  salt  on  the 
stomach.  Affections  of  the  respiratory  passages  are  not  produced  so 
often  by  the  bromides  as  by  the  iodides,  but  have  been  met  with,  and 
consist  in  an  increased  secretion  of  mucus  by  the  bronchial  and  nasal 
epithelium.  The  mental  symptoms  are  merely  exaggerations  of  those 
observed  after  one  large  dose.  The  memory  is  especially  defective, 
sometimes  sudden  lapses  occurring,  sometimes  a  general  inability  to 
remember  the  most  recent  events  being  met  with.  The  patient  is 
indifferent  to  his  surroundings,  speaks  slowly  and  stammers,  mispro- 
nounces ordinary  words  or  misses  several  words  out  of  a  sentence. 
The  gait  is  uncertain  and  tremor  often  accompanies  any  movement, 
the  expression  of  the  face  is  stupid  and  apathetic,  and  the  eyes  are 
heavy  and  lack  lustre. 

These  symptoms  generally  disappear  on  the  withdrawal  of  the  drug, 
but  in  his  reduced  condition  the  patient  is  of  course  liable  to  fall  a 
victim  to  infectious  disease,  and  in  a  number  of  cases  of  chronic  bromide 
poisoning  the  immediate  cause  of  death  has  been  an  attack  of  bronchitis 
or  pneumonia. 

Action. — The  effects  of  the  bromides  on  animals  can  be  examined  only 
by  the  use  of  sodium  bromide,  as  w^ien  the  potassium  salt  is  used,  the 
action  is  complicated  by  the  presence  of  potassium  effects,  which 
are  often  sufficient  to  obscure  the  slight  depression  of  the  brain  which 


202  SUBSTANCES  ACTING  AFTER  ABSORPTION 

is  the  really  characteristic  effect  of  the  bromide  ion.  In  the  frog,  for 
example,  potassium  chloride  is  capable  of  inducing  depression  of  the 
central  nervous  system,  and  the  slightly  greater  depression  induced 
by  the  bromide  may  well  be  overlooked;  it  appears,  however,  that 
bromides  have  very  little  true  depressant  action  on  the  frog.  The 
typical  bromide  action  may  be  induced  with  greater  clearness  in  mammals 
by  the  use  of  sodium  bromide  in  repeated  doses,  and  in  dogs  symptoms 
of  depression  and  imperfect  coordination  have  been  observed,  and  some- 
times stupor  and  death  from  failure  of  the  respiration;  the  symptoms 
of  central  nervous  depression  can  be  elicited  by  a  single  large  dose  in 
the  guinea-pig — lethargy,  incoordination  of  movements,  deep  sleep 
passing  into  coma  and  often  ending  in  death.  The  most  characteristic 
action,  however,  is  obtained  from  the  administration  of  the  drug  to 
patients,  as  the  affection  of  the  central  nervous  system  is  so  slight 
after  all  but  extreme  doses,  that  in  order  to  produce  distinct  symptoms 
in  the  less  sensitive  animals,  quantities  must  be  used  which  entail  the 
additional  complications  induced  by  salt-action. 

The  irritation  of  the  throat  and  stomach,  the  nausea,  vomiting  and 
rarer  diarrlura  must  be  attributed  for  the  most  part  to  the  action  of 
the  salt  in  withdrawing  fluid  from  the  mucous  membranes,  and  may 
be  avoided  by  the  use  of  dilute  solutions  and  by  their  administration 
when  the  stomach  is  full. 

The  depression  and  other  mental  symptoms  are  due  to  a  direct 
action  on  the  Central  Nervous  System.  Albertoni  found  that  the  irri- 
tability of  the  motor  areas  of  the  dog's  brain  was  very  distinctly 
reduced  by  the  administration  of  bromides,  and  in  particular  that  a 
stimulus  which  normally  would  have  spread  over  a  wide  area  and 
given  rise  to  an  epileptiform  convulsion,  caused  only  localized  con- 
tractions after  bromides,  while  convulsive  poisons  entirely  failed  to 
act.  Loewald  found  some  psychical  processes,  such  as  those  invohed 
in  the  addition  of  numbers,  uninfluenced  by  bromides,  while  a  series 
of  figures  could  be  learned  by  rote  only  with  great  difficulty;  he  there- 
fore considers  that  the  action  is  limited  to  certain  definite  functions. 
The  reflexes  are  also  reduced  very  considerably  by  bromides,  and 
according  to  many  observers  the  passage  of  impulses  from  the  sensory 
to  the  motor  cells  of  the  cord  is  interrupted,  while  the  connection 
between  the  cerebral  centres  and  the  motor  cells  of  the  cord  is  main- 
tained intact.  In  man  the  most  striking  instance  is  the  absence  of 
reflex  nausea  when  the  back  of  the  throat  is  touched.  While  reflex 
mo\'cments  cannot  be  elicited,  the  sensation  often  remains  unimpaired, 
but  after  large  doses  a  more  or  less  complete  anaesthesia  is  said  to  be 
produced.  This  anaesthesia  extends  to  the  skin  when  very  large  quan- 
tities are  administered,  and  the  cutaneous  sensation  is  said  to  be  blunted 
when  c()mi)aratively  small  doses  arc  taken;  the  action  is  purely  central, 
the  perii)heral  sense  organs  remaining  unail'ected. 

The  respiration  is  slower  uiuhr  i)romi(les,  owing  to  the  lessened 
movement,  but  is  scarcely  more  reduced  than  in  normal  sleej).  The 
sexual  instincts  are  depressed  or  entirely  sus])ended,  either  from  the 
action  on  the  brain  or  from  the  lessened  reflex  aeti\it\'. 


uromides  263 

The  bromide  ion  is  almost  as  indifferent  to  most  of  the  tissues  as  the 
chloride;  for  example,  muscle  and  nerve  live  almost  as  long  in  solutions 
of  sodium  bromide  as  in  those  of  the  chloride  of  equivalent  concentration. 
The  heart  may  be  perfused  with  saline  containing  bromide  instead  of 
chloride  for  many  hours  and  is  only  slightly  affected.  When  bromides 
are  given  by  the  mouth,  the  heart  is  not  affected;  potassium  bromide 
injected  intravenously  in  animals  is  poisonous  to  the  heart  as  are  the 
other  potassium  salts,  but  potassium  bromide  taken  by  the  mouth 
has  no  effect  on  the  heart.  The  vessels  of  the  pia  mater  have  been 
observed  to  be  contracted  under  the  bromides,  but  not  more  than  in 
normal  sleep,  and  this  antvmia  of  the  brain  is  the  result,  not  the  cause 
of  the  depression.  The  temperature  is  often  reduced  in  animals  under 
bromides  from  the  lessened  movement  and  consequent  lessened  produc- 
tion of  heat. 

The  skin  eruptions  arise  in  the  great  majority  of  cases  from  the 
glands,  and  in  fact  generally  remain  confined  to  them.  Bromide  has 
been  found  in  the  acne  pustules,  but  the  old  view  that  the  acne  is  due 
to  bromine  being  freed  in  the  glands  is  undoubtedly  incorrect. 

Distribution  and  Excretion. — The  bromides  are  rapidly  absorbed  by 
the  mucous  membranes,  and  some  bromide  reaction  can  be  obtained 
from  the  urine  a  few  minutes  after  they  have  reached  the  stomach. 
Their  distribution  in  the  body  resembles  exactly  that  of  the  chloride; 
thus  they  are  found  in  largest  amounts  in  the  blood  plasma  and  have 
little  tendency  to  accumulate  in  the  organs.  They  occur  in  all  the 
secretions  and  fluids  of  the  body;  they  may  be  found  in  the  form  of 
hydrobromic  acid  in  the  stomach,  and  traces  are  found  in  the  sweat 
and  milk  and  in  the  hair  where  chloride  occurs  naturally.  The  brain 
and  spinal  cord  do  not  contain  larger  quantities  than  the  other  organs 
and  never  approach  the  amount  contained  in  the  blood  plasma;  the 
skin  appears  to  contain  a  larger  amount  than  most  other  organs. 

The  whole  behavior  of  the  bromides  in  the  body  indicates  that  most  of 
the  tissues  are  unable  to  differentiate  them  from  the  normal  chloride  ions, 
and  react  to  a  dose  of  bromide  in  the  same  way  as  to  one  of  common 
salt.  Thus  the  administration  of  bromide  is  followed  by  the  excretion 
of  an  equivalent  amount  of  salt,  but  the  kidney  does  not  discriminate 
between  the  two  forms  circulating  in  the  blood  but  eliminates  a  mixture 
of  chloride  and  bromide  exactly  in  the  same  proportion  as  these  occur 
in  the  blood.  If  it  were  possible  to  follow  the  course  of  the  individual 
ions  in  the  body  after  a  dose  of  common  salt,  it  would  probably  be 
found  that  although  an  equivalent  amount  of  salt  is  soon  eliminated 
in  the  urine,  the  actual  chloride  ions  taken  would  only  be  represented 
in  this  excretion  to  a  limited  extent,  the  rest  being  furnished  by  that 
previously  present  in  the  blood  and  tissues;  the  rest  of  the  new  chloride 
would  gradually  be  eliminated  in  diminishing  proportions.  This  is 
what  occurs  in  the  nearly  related  bromides;  at  first  the  amount  excreted 
bears  a  high  proportion  to  that  of  the  chloride,  but  this  falls  off  rapidly 
and  some  bromide  appears  in  the  urine  for  long  afterward.  Thus, 
after  a  single  dose  of  30  grs.  the  urine  was  four.d  to  contain  bronnde 


2C)4       SUBSTANCES  ACTING  AFTER  ABSORPTION 

for  two  ijiuiiths,  only  ahout  10  pvT  cent,  being  eliminated  in  the  first 
24  honrs.  When  the  treatment  is  continued,  the  bromide  therefore 
tends  to  accumulate  in  the  body,  but  the  proportion  excreted  rises 
with  the  increase  of  the  salt  in  the  blood,  until  an  equiUbrium  is  reached, 
exactly  as  much  bromide  appearing  in  the  urine  as  is  absorbed  from  the 
stomach.  The  excretion  then  continues  long  after  the  treatment  is 
discontinued. 

When  the  body  is  thus  saturated  with  bromide,  the  blood  plasma  and 
ah  the  fluids  may  contain  as  much  bromide  as  chloride;  for  example, 
the  gastric  juice  may  contain  even  more  hydrobrominic  acid  than 
hydrochloric  acid.  The  bromides  are  not  simply  added  to  the  normal 
salts  of  the  blood,  but  supplant  the  chlorides,  which  are  excreted  in 
(piantity,  so  that  the  normal  salt  concentration  of  the  blood  is  main- 
tained, tiiough  the  chloride  is  much  diminished.  During  bromide 
treatment,  therefore,  and  especially  in  bromism,  not  only  is  there  an 
excess  of  bromide  in  the  body,  but  also  a  deficiency  of  chlorides,  and 
it  has  been  much  discussed  whether  the  symptoms  of  bromism  and  the 
sedati\-e  effects  of  bromide  arise  from  the  action  of  the  bromide  directly, 
or  are  the  results  of  the  deficiency  of  chloride.  In  favor  of  the  latter 
view,  it  is  urged  that  the  bromide  action  is  elicited  more  readily  when 
the  chloride  of  the  food  is  lessened,  and  that  the  addition  of  chloride 
to  the  dietary  often  relieves  the  symptoms  of  bromism  and  on  the  other 
hand  restores  the  epileptic  seizures  which  have  disappeared  under 
bromide  treatment.  And  Loeb  finds  that  certain  fish  are  depressed  in 
bromide  solution  but  remain  normal  if  chloride  is  added.  But  all 
of  these  observations  may  be  explained  by  the  acknowledged  fact  that 
the  administration  of  chloride  promotes  the  excretion  of  bromide  and 
thus  lessens  the  concentration  of  bromide  in  the  fluids  of  the  body. 
And  on  the  other  hand  it  is  found  that  animals  may  be  narcotized  with 
bromide  quite  rapidly,  long  before  it  is  possible  that  a  serious  fall  in 
the  chlorides  of  the  blood  has  occurred.  So  that  the  bromides  appear 
to  possess  a  definite  action  on  the  nerve  cells,  quite  apart  from  the 
deficiency  in  chlorides.  In  practice,  however,  the  bromide  action  is 
accompanied  by  chloride  poverty  and  on  the  other  hand  any  excess 
of  chloride  reduces  the  concentration  of  bromide  and  thus  interferes 
with  the  treatment.  The  same  is  true  of  other  measures  which  tend 
to  withdraw  bromide,  such  as  the  use  of  diuretics. 

The  bromides  of  sodium,  potassium  and  ammonium  have  identical 
effects  in  man  when  given  by  the  mouth.  In  animals  when  they  are 
injected  intravenously,  the  potassium  and  ammonium  bromides  may 
l)rcsent  in  addition  the  action  of  the  potassium  and  ammonium  ions. 

rUEI'ARATIONS. 

POTASSH  BmnuDUM  (U.  S.  p.,  B.  p.)    (KBr),  1  G.  (15  grs.);  B.  P.,  5-30  grs. 
Soon  BnoMinuM  (U.  S.  P.,  B.  P.)  (NaBr),  1  G.  (15  grs.);  B.  P.,  5-30  grs. 
Amwonu  lirtmidum  (U.  S.  P.,  B.  P.)  (NII^Br),  1  G.  (15  grs.);  li.  P.,  5-30  grs. 
Tlu!  iM-oinidcs  arc  all  colorless  crystalline  bodies  without  odor  but  willi  a 
.saliiio,  bitter  taste,  and  are  very  soluble  in  water.     They  are  almost  always 


BROMIDES  2G5 

prescribetl  iu  solution,  which  may  be  flavored  with  some  aromatic  syrup;  tliey 
are  not  given  liypoderniically  owing  to  tlic  hirge  dose  necessary. 

A  number  of  other  bromide  combinations  are  used  in  tlici-aiieutics,  sucli  as 
the  hydrobromide  of  (luininc,  but  here  the  bromide  ion  is  jjreserit  in  very  small 
quantity  compared  with  the  alkaloid,  and  in  the  doses  used  in  therapeutics 
has  no  appreciable  effect.  In  monobromated  camphor  the  bromine  is  present 
in  a  different  form  and  no  bromide  ion  is  liberated,  and  the  bromine  in  this 
compound  seems  to  have  little  or  no  effect.  Sabromine,  the  dibrombehenate  of 
calcium  ( (C22H4i02Br2)2Ca),  has  been  introduced  as  a  substitute  for  the  alkali 
salts,  but  differs  from  them  in  being  stored  in  the  fatty  tissues  and  in  only  slowly 
freeing  the  bromide  ion.  It  has  not  been  proved  to  be  of  value,  linnuipin 
and  Brovieigon  and  other  bromine  compounds  have  not  ]:)roved  equal  to  the 
bromides  in  practice.  Strontium  bromide  and  hydrobromic  acid  are  quite 
superfluous. 

Therapeutic  Uses. — The  bromides  are  used  chiefly  in  the  treatment 
of  epilepsy,  in  which  they  cannot  be  replaced  by  any  other  drug,  and 
the  prognosis  of  which  has  been  entirely  changed  since  their  introduc- 
tion. In  a  few  cases  the  bromide  treatment  is  said  to  cure  epilepsy— 
the  attacks  do  not  return  after  the  treatment  is  stopped— but  this  is 
exceedingly  rare;  in  others  the  bromides  have  no  eft'ect,  but  in  the 
great  majority  of  cases  (90-95  per  cent.)  the  number  of  attacks  is 
much  smaller,  or  the  patient  may  be  entirely  free  from  them  as  long 
as  the  treatment  is  persevered  with,  although  they  return  as  soon  as  it 
is  given  up.  Very  often  no  improvement  is  observed  during  the  first 
few  days,  until  the  tissues  have  become  saturated  with  bromide,  but 
in  other  cases  the  spasms  disappear  immediately.  The  bromide  of 
potassium  is  more  commonly  used  than  the  others,  and  the  general 
impression  is  that  it  is  more  efficient  and  more  certain  in  its  effects, 
but  some  physicians  prefer  the  bromide  of  ammonium  or  of  sodium, 
and  others  still  prefer  a  mixture  of  two  bromides.  In  severe  cases  it 
is  sometimes  found  that  the  bromide  action  is  strengthened  by  the 
addition  of  cannabis  indica,  opium  or  chloral,  although  the  last  two 
are  to  be  used  with  caution.  In  the  treatment  of  epilepsy  it  is  well 
to  begin  with  small  doses  and  to  increase  them  up  to  10  G.  per  day, 
or  until  the  desired  effect  is  attained,  or  some  complication,  such  as 
widespread  skin  affections,  precludes  their  further  use.  When  little 
chloride  is  taken  in  the  food,  the  excretion  of  bromine  is  much  retarded, 
and,  on  the  other  hand,  the  addition  of  chloride  to  the  dietary  accel- 
erates the  bromide  excretion.  The  restriction  of  the  salt  in  the  food 
of  epileptics  under  bromide  treatment  has  therefore  been  suggested 
with  the  object  of  saturating  the  tissues  with  smaller  doses  of  bromide 
than  would  otherwise  be  necessary.  In  practice,  however,  it  is  difficult 
to  reduce  materially  the  chlorides  of  the  food,  and  equally  satisfactory 
results  may  be  obtained,  with  less  hardship  to  the  patient,  by  slightly 
increasing  the  dose  of  bromide.  The  use  of  bromide  has  to  be  continued 
for  many  months  or  years  in  epilepsy  and  the  aim  should  be  to  reduce 
the  dose  to  the  lowest  efficient  one  and  to  maintain  this  without  variation. 
It  may  also  be  useful  to  keep  the  chloride  of  the  food  fairly  constant 
and  to  avoid  any  treatment  which  may  disturb  the  concentration  of 
bromide  in  the  blood,  such  as  diuresis  or  violent  purgation. 


200  SUBSTANCES  ACTING  AFTER  ABSORPTION 

T\\v  aciR'  is  \-(Ty  often  a  tr()ul)les()nie  accompaniment  of  the  bromide 
action,  and  in  fact  nia\'  |)re\T'nt  the  use  of  this  vahiable  drug  in  other- 
wise snital)lc  cases.  It  may  often  be  prevented  by  scrupulous  cleanU- 
ness  of  the  skin,  and  frequently  yields  to  treatment  with  small  doses 
of  arsenic. 

The  bromides  are  not  so  efi'ective  in  other  afi'ections  of  the  central 
nervous  system,  although  some  success  has  attended  their  use  in  chorea, 
in  the  convulsions  of  children,  and  in  some  form  of  hysteria.  They 
have  also  been  used  in  tetanus  and  in  strychnine  poisoning,  but  are 
inferior  to  other  remedies,  such  as  chloral.  Neuralgia  is  sometimes 
improved  by  bromide  treatment,  especially  when  it  arises  from  worry, 
anxiety,  or  overwork. 

As  soporifics,  bromides  often  fail  entirely,  or  induce  such  depression 
and  confusion  subsequently  as  to  preclude  their  use.  This  prolonged 
action  doubtless  arises  from  the  slow  excretion  of  the  bromide,  the  great 
proportion  of  that  taken  remaining  in  the  tissues  for  more  than  24  hours. 
In  sleeplessness  from  anxiety  they  are  often  valuable,  however,  and 
it  is  found  that  the  dose  of  chloral  may  be  considerably  lessened  if  it  is 
prescribed  along  with  bromides.  In  sleeplessness  from  pain  bromide  is 
of  little  or  no  value.  The  bromides  are  little  suited  for  use  in  a  single 
dose  unless  it  be  a  large  one.  On  the  other  hand  their  very  prolonged 
action  is  very  valuable  in  cases  of  exaltation  and  nervousness  in  which 
it  is  desired  to  allay  the  excitability  without  causing  actual  sleep,  and  in 
which  an  immedite  effect  is  not  so  necessary  as  a  prolonged  slight  action. 

Bromides  have  been  used  with  good  results  in  sea-sickness,  in  the 
sickness  of  pregnancy,  and,  it  is  said,  in  whooping  cough. 

Bibliography. 

Krosz.    Arch.  f.  exp.  Path.  u.  Pharm.,  vi,  p.  1. 
Albertoni.     Ibid.,  xv,  p.  248. 

Loewald,  Ach.  KraepeHn's  Psycholog.  Arb.,  i,  p.  489;  iii,  p.  203. 
Wiersma.    Ztsch.  f.  Psych,  u.  Phys.  d.  Sinnesorgane,  xxviii,  p.  179. 
Heffter.    Ergebnisse  der  Physiologic,  ii,  1,  p.  102. 

V.  Wyss.  Arch.  f.  exp.  Path.  u.  Pharm.,  Iv,  p.  26G;  lix,  p.  189.  Deutch.  med.  Woch., 
1913,  p.  345. 

Amory.    Bromide  of  Potassium  and  Bromide  of  Ammonium,  Boston,  1872. 

Hale  and  Fishman.    Amer.  Jour,  of  Physiol.,  xxii,  p.  32. 

Ellinger  and  Kolakc.    Arch.  f.  exp.  Path..  Ixv,  p.  87. 

Janusr.hke  and  Inaba.    Zeitschr.  f.  d.  ges.  exp.  Med.,  i,  p.  129. 

Bonniger     Zeitschr.  f.  exp.  Path.,  u.  Ther.,  vii,  p.  556. 

Bernoulli.     Arch.  f.  exp.  Path.  u.  Pharm.,  Ixxiii,  p.  353. 

V.      STRYCHNINE     NUX  VOMICA. 

Strychnine  is  the  chief  alkaloid  occurring  in  se\'eral  species  of 
Strychnos,  of  which  the  best  known  are  Strychnos  nux  vomica  and 
Strychnos  Ignatia.  It  is  found  chiefly  in  the  seeds,  and  is  generally 
accompanied  by  tlic  nearly  related  alkaloid  Jlriicine. 

A  larso  iminber  of  alkaloids  have  been  found  to  rescMublo  .strychnine  in 
their  action,  such  as  the  Thchainc  found  in  opium,  and  the  (ichciiiinc  of  (!clse- 
rniuni  .scmpcrvirens,  while  it  is  difHcult  to  (lcci(h>  wlu't  her  several  otliers  outiht 
to  be  clas.sed  with  morpliinc  or  witli  strychnine. 


STRYCHNINE— NUX    VOMICA  267 

Strychnine  seems  to  be  a  quinoline  derivative,  altliough  its  exact  constitution 
is  luiknown.  Its  formula  is  C21H22N2O2,  while  that  of  brucine  is  C23H26N2O4. 
They  are  both  derivatives  of  a  substance  of  the  formula  C15H17N2O2,  brucine 
differing  from  strychnine  in  having  two  methoxyl  groups.  It  seems  not 
unlikely  that  they  are  both  nearly  related  to  curarine,  the  alkaloid  of  curara, 
which  is  derived  from  some  other  species  of  the  genus  Strychnos. 

The  alkaloids  of  the  strychnine  group  have  a  powerful  stimulant 
action  on  the  central  nervous  system,  especially  on  the  spinal  cord, 
throughout  the  vertebrate  kingdom. 

Symptoms. — In  ordinary  therapeutic  doses  strychnine,  like  other 
bitter  substances  (page  51),  improves  the  appetite  and  often  leads  to 
a  distinct  amelioration  of  the  subjective  symptoms,  the  patient  feeling 
stronger  and  more  hopeful.  The  special  senses  are  rendered  more 
acute  by  small  quantities  of  strychnine,  for  differences  can  be  recog- 
nized between  shades  of  color  which  seem  identical  to  the  normal 
vision;  the  field  of  vision  is  widened,  and  in  certain  conditions  of 
ambhopia  light  is  rendered  much  more  distinct.  In  the  same  way 
the  hearing  seems  to  be  more  acute,  and  the  sense  of  touch  is  much 
more  delicate.  Some  cases  have  been  noted  in  which  disagreeable 
odors  were  rendered  pleasant  by  strychnine,  but  this  would  seem  to 
be  a  rare  idiosyncrasy.  In  larger  doses  strychnine  increases  the  reflex 
movements,  and  the  sense  of  touch  is  rendered  distinctly  more  acute. 

Fig.  15 


A  rabbit  during  a  strychnine  convulsion. 

In  cases  of  poisoning  with  strychnine,  these  effects  are  present  but 
are  not  generally  observed  by  the  patient,  whose  first  complaint  is  of  a 
feeling  of  stiffness  in  the  muscles  of  the  neck  and  face.  This  is  soon 
followed  by  an  increased  reflex  reaction,  so  that  a  slight  touch  causes  a 
violent  movement,  and  even  a  sound  or  a  current  of  air  is  sufficient  to 
cause  a  sudden  start.  The  increased  reflex  irritability  is  generally 
accompanied  by  some  restlessness,  and  animals  sometimes  seem  to  make 
attempts  to  escape  from  bright  light.  Some  tremor  or  involuntary 
twitches  may  be  observed  in  the  limbs,  and  then  a  sudden  convulsion 
occurs  in  which  all  the  muscles  of  the  body  are  involved,  but  in  which 
the  stronger  extensor  muscles  generally  prevail.  In  animals  the  head 
is  drawn  back,  the  hind  limbs  extended,  and  the  trunk  forms  an  arch 
with  its   concavity  backward  (opisthotonos)   (Fig.  15).     In  man   the 


X 


2GS  SUBSTANCES  ACTING  AFTER  ABSORPTION 

same  convulsions  are  seen  and  are  accompanied  by  strong  contraction 
of  the  face  muscles,  producing  a  hideous  grin  which  lias  been  called 
the  r/.v//,s'  sardonic  us.  The  resi)irat()ry  muscles  are  involved  in  the 
general  paroxysm  and  the  l)lood  rapidly  becomes  deoxygenated,  as  is 
shown  by  the  blue,  cyanotic  color  of  the  lips  and  face  in  man.  The 
muscles  feel  hard  and  firm  at  the  commencement  of  the  convulsion, 
but  very  soon  a  tremor  may  be  made  out,  which  becomes  more  distinct, 
and  after  a  few  intermittent  contractions  the  animal  sinks  back  in 
a  condition  of  prostration  (Fig.  16).  The  respiration  generally  returns, 
and  becomes  fairly  regular  for  a  short  time.  Immediately  after  a 
convulsion  the  reflex  irritability  may  be  low,  but  it  soon  regains  its 
former  exaggerated  condition  and  a  second  convulsion  occurs,  exactly 
resembling  the  first.  IVIammals,  as  a  general  rule,  succumb  after  two 
or  three  convulsions,  the  respiration  failing  to  return  after  the  spasm. 

Fig.   10 


A  rabbit  when  the  strychnine  spasm  is  passing  off.     The  head  is  supported  to  prevent 

it  falling  on  the  table. 

In  some  cases,  however,  the  convulsions  become  shorter  and  the  intervals 
of  quiescence  longer,  the  respiration  becomes  weak,  the  reflex  irritability 
gradually  lessens  and  the  animal  dies  from  asphyxia.  In  frogs,  where  the 
breathing  can  be  dispensed  with  for  long  periods,  the  alternation  of 
convulsions  and  periods  of  quiescence  may  continue  for  hours  or  days, 
but  these  are  of  the  same  general  character  as  those  described  in  mam- 
mals. After  very  large  quantities  no  convulsions  may  occur,  the  animal 
dying  almost  immediately  of  asphyxia  from  paralysis  of  the  central 
nervous  system. 

Action. — The  whole  character  of  the  intoxication  points  to  an  affec- 
tion of  the  Central  Nervous  System,  and  it  has  been  found  that  the 
synii)tonis  arc  unaltered  when  the  drug  is  prevented  from  reaching  the 
l^eriplieral  nerves  and  muscles.  The  chief  symptoms  arise  from  the 
spinal  cord,  for  the  convulsions  are  at  least  as  well  marked  in  frogs 
and  mammals  in  which  the  brain  has  been  destroyed  or  severed  below 
the  medulla  oblongata.  The  intellect  in  man  remains  unclouded  until 
the  end,  except  for  the  asphyxia  i)roduced  by  the  stoppage  of  the 
respiration;  the  i)atient  is  perfectly  conscious  of  his  condition,  and 
sutters  excruciating  pain  from  the  violent  contractions  of  the  muscles. 

The  s[)ecial  senses  are  rendered  more  acute  by  small  doses  of  strych- 
nine, and  this  is  apparently  due  to  its  ett'ects  on  the  central  nervous 


STRYCHNINE— MUX   VOMICA  209 

system  in  the  case  of  touch,  taste  and  smell,  but  there  is  reason  to 
beheve  that  the  increase  in  the  field  of  vision  and  the  increased  sensi- 
tiveness to  slight  differences  in  light  are  to  be  attributed  to  its  acting 
on  the  cells  of  the  retina  and  not  to  cerebral  changes.  For  when 
strychnine  salts  are  injected  in  the  temple  or  applied  to  the  conjunc- 
tiva, the  sight  of  the  corresponding  eye  is  improved  while  the  other 
remains  unaffected  (Filehne);  if  the  strychnine  acted  centrally  it 
could  do  so  only  by  being  carried  to  the  brain  by  the  blood,  but  this 
would  affect  each  hemisphere  equally.  The  affection  of  one  eye  only 
is  explained  by  the  strychnine  diffusing  through  the  lymph  spaces, 
and  this  is  said  to  have  occurred  in  the  case  of  various  dyes  which 
were  applied  in  the  same  way  and  were  then  found  in  the  retina. 

Ergographic  experiments  have  shown  that  small  doses  of  strychnine 
augment  the  capacity  for  muscular  work  to  a  considerable  degree, 
and  delay  the  onset  of  fatigue;  this  excitation  phase  is  followed  by 
one  in  which  the  capacity  is  lowered.  Electrical  stimulation  of  the 
motor  areas  of  the  brain  is  more  effective  under  strychnine  than  in 
unpoisoned  animals,  but  this  does  not  necessarily  indicate  that  the  cells 
of  these  areas  are  acted  on  directly,  for  the  same  apparent  increased 
irritability  of  the  cortical  areas  is  seen  when  the  poison  acts  on  the 
cord  only,  and  it  may  therefore  be  the  result  of  the  spinal  action. 

The  convulsions  are,  as  has  been  stated,  of  spinal  origin. ^  It  has 
been  shown  in  addition  that  they  are  reflex,  that  provided  no  stimulus 
reaches  the  cord  from  without,  no  convulsion  occurs.  As  has  been 
9,lready  remarked,  the  convulsions  are  preceded  by  a  stage  of  increased 
reflex,  and  in  fact  the  first  convulsion  is  often  seen  to  follow  a  stimulus, 
such  as  a  blow  or  a  loud  noise.  Afterwards  they  may  seem  to  occur 
without  any  such  impulse,  but  this  is  merely  because  a  very  slight  or 
even  imperceptible  stimulus  is  enough  to  induce  them.  For  example, 
a  slight  contraction  of  a  muscle  may  induce  a  convulsion,  as  is  seen 
very  frequently  in  the  frog,  where  a  very  slight  stimulus,  in  itself 
apparently  too  weak  to  cause  a  convulsion,  is  followed  by  an  ordinary 
reflex  contraction,  and  this  leads  to  a  spasm.  The  absence  of  con- 
vulsions when  external  stimuli  are  cut  off  may,  however,  be  demon- 
strated conclusively  in  various  ways.  Thus  Poulsson  found  that  a  frog 
dipped  in  cocaine  solution  undergoes  no  convulsions  after  strychnine, 
the  cocaine  used  being  sufficient  to  paralyze  the  sensory  terminations, 
but  not  to  have  any  direct  effect  on  the  cord.  Claude  Bernard  showed 
this  even  more  conclusively  by  dividing  all  the  posterior  roots  of  the 
spinal  nerves  in  the  frog  and  then  injecting  strychnine,  when  no  con- 
vulsions occurred  except  when  the  ends  of  the  cut  roots  were  stimulated. 
The  convulsions  therefore  follow  only  on  the  passage  of  an  impulse  from 
without  to  the  spinal  cord,  and  are  merely  a  further  development  of  the 
preceding  stage  of  exaggerated  reflex  irritability. 

The  characteristic  feature  of  strychnine  poisoning  is  thus  the  changed 

'  In  this  term  is  included  not  only  the  spinal  cord  proper,  but  also  those  parts  of  the 
brain  which  correspond  to  the  cord  in  performing  simple  reflex  movements. 


270 


SUnSTAXCES   ACTIXd   AFTER   ABSORPTION 


Fig.  17 


response  to  external  stimuli.  In  the  uni)oisoned  animal  the  reflex 
movement  following  a  stimulus  is  always  of  the  same  kind;  for  example, 
if  the  leg  of  a  decapitated  frog  be  dipped  in  acid  it  makes  certain  move- 
ments to  withdraw  the  limb,  and  no 
matter  how  often  the  irritation  be  re- 
peated, the  same  movements  are  produced, 
though  it  is  true  that  if  stronger  acid  be 
used  the  movement  is  more  violent  and 
a  greater  number  of  muscles  are  involved. 
In  this  movement  certain  muscles  con- 
tract while  their  antagonists  are  inhibited ; 
for  example,  in  drawing  the  toe  away  from 
an  irritant  the  anterior  muscles  of  the  leg 
contract,  while  the  gastrocnemius  is  re- 
laxed. The  same  irritation  which  pro- 
duced in  the  unpoisoned  animal  a  simple 
withdrawal  of  the  limb,  causes  after 
strychnine  stronger  and  more  extensive 
contractions,  and  the  movement  is  not 
confined  to  the  two  hind  legs  but  spreads 
over  the  whole  body.  All  the  muscles 
contract  together,  there  being  no  inhibi- 
tion of  antagonists,  and  the  resultant 
movement  has  thus  quite  a  different  char- 
acter; the  gastrocnemius  being  stronger 
than  the  anterior  leg  muscles,  the  foot  is 
extended  and  thrust  against  the  irritant 
instead  of  being  withdrawn  from  it.  This 
change  in  the  character  of  the  reflex 
movement  has  been  the  subject  of  careful 
investigation  by  Sherrington,  who  finds 
that  in  mammals  a  stimulus  which  nor- 
mally causes  inhibition  of  a  muscle,  causes 
contraction  under  strychnine.  This  re- 
versal occurs  whether  the  stimulus  is 
derived  from  the  ])eriiiluTy  and  the  con- 
sequent movement  is  a  reflex  one,  or  from 
the  brain.  In  both  cases  the  reversal  of 
the  character  of  the  movement  arises  from 
changes  in  the  spinal  cord,  the  impulse 
from  the  brain  or  jxTiphery  bearing  its 
normal  character,  but  changing  its  nature 
in  passing  through  the  cord.  It  is  some- 
times states]  that  the  inhibitory  imi)ulse 
is  actuall\'  changed  to  a  motor  one,  but 
this  is  not  necessarily  the  case;  lor  it 
seems  ])robable  that  e^'ery  im])ulse  reach- 
ing the  cord  is  in  i):irt  inhibitory,  in  part 


Diagram  of  the  spinal  cord  of 
the  frog.  A-B,  the  part  of  the  cord 
exposed  to  strychnine.  B-C,  the 
unaffected  zone.  An  impulse 
reaching  the  cord  through  the  sen- 
sory fibre  E  passes  to  the  motor 
cells  FP'  and  induces  an  ordinary 
reflex  movement,  showing  that  the 
(•(•lis  FF  are  not  altered  by  strych- 
nine. On  the  other  hand,  an  im- 
pnls'  reaching  the  cord  through 
the  sensory  fii)rc  J)  causes  tetanic 
i-<)n\'uisi()iis  nut  only  in  the  muscl(>s 
supplied  by  the  motor  cells  /'"/'", 
which  an^  under  the  influence  of 
the  i)oiHon,  but  also  in  those  sup- 
plied by  /''/'',  which  have  been 
shown  to  be  free  from  the  strych- 
nine action. 


STRYCHNINE— NUX   VOMICA  271 

motor,  but  in  the  unpoisoned  animal  the  inhibitory  factor  prevails  while 
in  strychnine  poisoning  the  motor  predominates.  The  strychnine  may 
thus  merely  increase  the  motor  element  in  the  impulse  without  actually 
reversing  the  inhibitory  one. 

When  an  external  stimulus  is  sufficient  to  cause  a  convulsive  move- 
ment in  a  poisoned  animal,  the  contraction  is  always  maximal;  a 
stronger  stimulus  produces  no  greater  effect. 

There  are  strong  grounds  for  the  belief  that  the  cells  of  the  anterior 
horn  are  not  necessarily  involved  in  the  strychnine  action  (Fig.  17). 
For  when  strychnine  is  applied  in  solution  to  the  cord  of  the  frog  at 
the  level  of  the  cells  connected  with  the  nerves  to  the  fore  limbs,  irri- 
tation of  the  hind  foot  produces  an  ordinary  response  in  the  hind  limbs, 
while  the  anterior  part  of  the  body  remains  motionless;  that  is,  strych- 
nine has  not  penetrated  to  the  cells  connected  with  the  hind  limbs. 
Irritation  of  the  fore  limbs,  on  the  other  hand,  produces  tetanus  not 
only  of  these,  but  also  of  the  hind  limbs,  although  the  motor  cells  of 
the  hind  limbs  have  been  shown  to  be  outside  the  poisoned  area. 
Tetanus  can,  therefore,  be  produced  in  parts  whose  motor  cells  are 
unpoisoned.  The  increased  strength  of  the  contraction  is  due,  not  to 
augmented  energy  in  the  anterior  horn  cell,  but  to  the  impulses  which 
these  receive  being  much  stronger.  This  experiment  suggests  further 
that  the  synapse  round  the  motor  cell  is  not  the  point  chiefly  affected 
by  strychnine.  And  the  posterior  root  ganglion  is  not  the  seat  of 
action,  for  convulsions  may  be  elicited  by  stimulation  of  the  posterior 
roots  above  this  point.  The  action  may  thus  be  localized  in  some 
point  between  the  entrance  of  the  afferent  fibre  and  the  synapse  round 
the  motor  cell.  The  depressants  of  the  alcohol-chloroform  group 
appear  to  act  at  the  same  point  as  strychnine  (p.  199).^ 

An  impulse  travelling  up  a  nerve  in  an  unpoisoned  frog  reaches  the 
cord  and  may  there  pass  through  a  number  of  paths  and  in  each  is 
subjected  to  various  influences,  so  that  it  arouses  different  motor  cells 
to  different  degrees  of  activity,  or  actually  inhibits  the  activity  of  some 
of  them;  in  this  way  a  coordinated  movement  follows.  Under  strych- 
nine these  influences,  which  may  be  figured  as  varying  resistances  in 
the  different  paths,  disappear,  and  the  impulse  passes  untrammeled 
along  all  available  paths  and  reaches  the  motor  cells  in  much  greater 
force  than  normally  and  thus  arouses  a  more  powerful  reaction  from 
them  and  a  correspondingly  strong  muscular  contraction.  But  the 
resistance  in  the  different  paths  is  essential  to  coordinate  the  move- 
ment and  the  increased  muscular  contraction  is  thus  no  longer  coor- 
dinated, all  the  muscles  contracting  together  and  the  character  of  the 
movement  being  determined  by  their  relative  strength.  The  action 
of  strychnine  may  thus  be  explained  by  supposing  that  it  removes 

1  Several  investigators  (Ryan,  McGuigan,  Barenue)  have  thrown  some  douljt  recently 
upon  this  view  of  strychnine  action,  and  claim  that  their  experiments  on  mammals  indi- 
cate that  the  motor  cells  are  also  involved  in  the  strychnine  action  and  that  convulsions 
arise  only  when  the  drug  reaches  the  anterior  horn  cells.  The  subject  requires  further 
investigation. 


■272  SUBSTANCES  ACTING  AFTER  ABSORPTION 

resistances  to  the  passages  of  impulses  through  some  of  the  synapses  of 
the  spinal  cord  and  thus  extends  the  area  on  which  an  impulse  acts, 
and  also  liberates  it  from  the  normal  coordinating  influences. 

It  must  be  remarked  that  while  the  resistance  is  much  reduced,  it 
is  not  entirely  removed,  and  the  ordinary  path  is  still  somewhat  more 
easily  traversed  than  the  others,  for  very  weak  irritation  often  causes 
an  ordinary  reflex  response  in  the  frog,  while  a  slightly  stronger  stimulus 
throws  it  into  opisthotonos.  Baglioni  has  shown  that  a  single  stimulus 
is  not  sufficient  to  cause  complete  tetanus,  but  that  the  movement 
induced  by  the  first  shock  leads  to  secondary  stimuli  arising  from  the 
joints  and  tendons  which  are  moved;  the  arrival  of  these  secondary 
stimuli  in  the  cord  maintains  it  in  activity,  and  the  muscles  conse- 
quently remain  contracted  until  the  cord  is  fatigued  and  refuses  to 
react  to  the  persistent  stimuli  from  the  periphery.  The  muscles  then 
relax  and  an  interval  of  quiescence  follows  until  the  cord  has  recovered 
its  irritability. 

Besides  the  spinal  cord,  all  other  regions  in  which  simple  reflexes  can 
be  produced,  are  affected  by  strychnine.  Thus  the  medullary  centres 
are  thrown  into  the  same  condition,  and  their  responses  to  stimuli  are 
equally  exaggerated;  but  they  are  in  constant  receipt  of  impulses,  and 
strychnine,  by  increasing  the  eflSciency  of  these,  augments  the  tone  of 
the  medulla  oblongata,  when  it  is  given  in  small  quantities. 

Artificial  respiration  has  been  shown  to  delay  the  onset  of  convul- 
sions in  animals,  but  it  is  still  an  open  question  whether  this  is  due  to 
the  better  aeration  of  the  blood  (Osterwald)  or  to  the  effects  of  the 
mechanical  movements  (Gies  and  Meltzer). 

The  stimulation  of  the  spinal  cord  by  strychnine  is  followed  by 
depression  and  paralysis.  Even  during  the  first  stage  the  stimulation 
is  mixed  with  depression,  for  though  a  more  violent  response  is  induced 
by  a  sensory  stimulus,  this  cannot  be  repeated  so  often  as  in  the  normal 
frog,  as  the  cord  becomes  fatigued  more  readily.  The  sensory  part  of  the 
spinal  cord  seems  to  be  paralyzed  somewhat  earlier  than  the  motor 
cells,  but  these  also  lose  their  irritability  after  a  time  and  no  further 
movement  can  be  elicited  either  by  reflex  or  by  direct  stimulation  of  the 
cord. 

Strychnine  seems  to  have  no  direct  action  on  the  voluntary  Muscles; 
it  is  stated  that  minute  quantities  increase  their  tone,  that  is,  render 
them  more  tense,  so  that  they  are  prepared  for  immediate  contraction, 
but  this  is  due  to  action  on  the  cord  and  not  on  the  muscle  fibres. 

The  Terminations  of  the  Motor  Nerves  are  paralyzed  by  large  doses 
of  strychnine  in  the  same  way  as  by  curara.  This  efl'ect  is  scarcely 
seen  in  mammals,  as  central  paralysis  always  precedes  it  and  destroys 
life,  but  in  some  species  of  frogs  the  nerve  ends  are  paralyzed  before 
the  central  nervous  system.  This  paralysis  is  not  due  to  the  exhaustion 
of  the  ii('r\'e  ends  through  the  tetanus,  but  is  a  direct  action  on  the 
(crniiiiiitioiis,  jiltliough  the  exhaustion  may  contribute  to  the  result. 

The  Respiration  is  (luickeneil  by  small  (luantities  of  strychnine,  espe- 
cially when  tin-  centre  is  depressed  by  the  previous  administration  of 


STRYCHNINE—NUX   VOMICA 


273 


a  narcotic.  During  the  convulsions  the  breathing  is  arrested  by  the 
violent  contractions  of  the  diaphragm  and  the  other  respiratory  muscles, 
but  during  the  intermissions  it  continues  fairly  regular.  After  one  or 
two  spasms  it  often  fails  to  be  reinstated,  and  the  animal  dies  of  asphyxia; 
in  other  experiments  it  undergoes  a  gradual  diminution  in  rate  and 
strength,  and  eventually  ceases  from  gradual  paralysis  of  the  centre. 
A  reversal  of  the  respiratory  reflexes  is  sometimes  seen  after  large 
doses  in  animals  and  is  analogous  to  that  described  in  the  inhibitory 
reflexes  of  the  spinal  cord. 

Fig.  18 


v^('•«'%»4v^*^*''*^*^^ 


v/' 


'^«/^/^' 


Tracings  of  the  blood-pressure  (upper)  and  intestinal  volume  (lower)  from  a  curarized 
cat,  showing  the  effect  of  the  intravenous  injection  of  a  dose  of  strychnine  sufficient  to 
cause  spasms  in  an  uncurarized  animal.  The  blood-pressure  rises,  while  the  mesenteric 
vessels  are  contracted  from  spasm  of  the  vasomotor  centre  (Bayliss). 


The  Heart  is  not  directly  affected  by  strychnine  in  mammals,  though 
it  is  sometimes  slightly  slowed  by  stimulation  of  the  inhibitory  centre. 
During  and  after  a  convulsion  it  may  be  accelerated  as  in  violent 
exertion  from  any  cause.  Very  large  quantities  slow  and  weaken  the 
frog's  heart. 

The  Vasomotor  Centres  are  stimulated  by  small  quantities,  so  that 
the  splanchnic  vessels  are  constricted,  while  the  cutaneous  and  perhaps 
18 


274  SUBSTANCES  ACTING  AFTER  ABSORPTION 

the  muscular  vessels  tend  to  dilate  from  stimulation  of  the  vasodilator 
centre.  The  blood  is  thus  deflected  to  some  extent  from  the  internal 
organs  to  the  skin  and  limbs.  Larger  quantities  tend  to  disorganize 
the  vasomotor  centre  in  a  way  analogous  to  that  described  in  the  spinal 
cord,  for  Bayliss  finds  that  inhibitory  reflexes  involving  the  vasomotor 
centre  are  changed  to  motor  ones;  thus  stimulation  of  the  depressor 
nerve  after  strychnine  causes  a  rise  in  blood-pressure. 

During  the  convulsions  the  blood-pressure  is  raised  to  an  extreme 
height,  partly  owing  to  the  activity  of  the  vasomotor  centre  and 
perhaps  ])artly  from  the  blood  being  pressed  out  of  the  abdominal 
organs  and  the  muscles  by  the  violent  contractions.  Immediately 
after  a  convulsion  the  blood-pressure  falls,  probably  from  the  exhaus- 
tion of  the  centre.  The  blood-pressure  remains  elevated  much  longer 
in  curarized  than  in  uncurarized  animals,  which  would  seem  to  indicate 
that  the  fall  in  pressure  is  partly  due  to  the  substances  produced  by 
muscular  activity. 

In  the  Alimentary  Tract,  strychnine  has  the  same  action  as  any 
other  bitter  substance,  and  it  produces  a  flow  of  saliva  and  increased 
appetite  if  taken  before  meals.  (See  Stomachic  Bitters,  page  51).  It 
seems  to  be  absorbed  from  the  intestine  mainly.  After  absorption  it 
is  said  to  increase  the  movements  of  the  bowel  from  some  action  on 
the  muscle  or  on  the  ganglionic  plexus  in  the  bowel  wall. 

Metabolism. — Strychnine  produces  an  enormous  activity  of  the  mus- 
cles, and,  therefore,  increases  very  greatly  the  consumption  of  oxygen 
and  the  output  of  carbonic  acid.  This  is  accompanied  by  an  increased 
formation  of  heat,  which  would  lead  to  a  rise  in  the  temperature  of  the 
body  were  it  not  counteracted  by  an  equal  or  even  greater  increase 
in  its  dissipation  through  the  skin.  As  a  result  the  temperature  is 
generally  lowered  in  rabbits,  while  it  sometimes  rises  slightly  in  dogs 
and  cats.  The  skin  temperature,  on  the  other  hand,  rises  considerably 
l)ecause  more  blood  flows  through  it  than  usual. 

Glycosuria  occurs  in  frogs  and  in  young  mammals,  and  the  glycogen 
of  the  liver  and  muscles  disappears  in  most  animals  under  strychnine; 
the  increased  muscular  movement  and  the  disturbance  of  the  respiration 
are  probably  the  explanation  of  both  of  these  phenomena. 

Strychnine  is  eliminated  in  the  urine  chiefly.  Its  excretion  begins 
three  hours  after  its  injection,  but  is  exceedingly  slow,  and  the  reaction 
is  often  given  by  the  urine  for  three  to  eight  days  afterward.  Traces 
of  the  alkaloid  also  appear  in  the  stomach  after  its  hyjxxlemiic  injec- 
tion, and  it  is  not  improl)able  that  some  of  it  undergoes  oxidation  in 
the  tissues.  Only  a  very  slight  degree  of  tolerance  is  developed  for 
strychnine,  even  after  very  prolonged  administration. 

'V\h:  action  of  strycliniiK!  i.s  almost  iilculii-al  thi(»u.t;liout  the  vertebrate 
kiii<!;<loiii.  Man  is  more  sus('e|)til)lc  than  other  luamnials,  and  young  animals 
arc  more  refractory  than  a(hilts,  }K>rhai)s  owinfz;  to  the  less  (lcvcloi)cd  condition 
of  the  central  nervous  system.  Tlic  domestic  fowl  tolerates  comparatively 
larger  (juant it ics  without  symj)toms.  The  characteristic  convulsant  action  is 
not  elicited  in  most  invertebrates,  in  wliich  it  generally  induces  paralysis  only. 


STRYCHNINE— NUX   VOMICA  275 

Brucine,  the  second  alkaloid  of  nux  vomica,  resembles  strychniue  closely 
in  action  but  is  much  weaker,  from  30  to  40  times  as  large  a  dose  being  required 
to  produce  the  same  effect.  It  differs  from  stryclinine  also  in  possessing  a  much 
more  powerful  action  on  the  nerve  terminations  in  voluntary  muscle,  especially 
in  some  species  of  frog.    It  is  credited  with  weak  local  anesthetic  properties. 

Preparations. 

Nux  Vomica  (U.  S.  P.,  B.  P.),  the  seeds  of  Strychnos  nux  vomica,  contains 
not  less  than  1.25  per  cent,  of  strychnine  along  with  brucine  (0.7-1.5  per  cent.) 
and  tannin,  which  gives  a  dark  green  coloration  with  iron  salts.  Dose  0.065  G. 
(1  gr.);  B.  P.,  1-4  grs.  The  preparations  are  assayed  to  a  definite  strength  of 
strychnine. 

ExTRACTUM  Nucis  VoMiCE  (U.  S.  P.,  B.  P.),  5  per  cent.,  0.015  G.  (i  gr.); 
B.  P.  i-1  gr. 

TiNCTURA  Nucis  VoMiCiB  (U.  S.  P.,  0.1  per  cent.),  (B.  P.,  0.125  per  cent.), 
0.6  c.c.  (10  mins.);  B.  P.,  5-15  mins). 

Strychnine  Nitras  (U.  S.  P.),  0.001  G.  {eh  gr.). 

Strychnine  Hydrochloridum  (B.  P.),  itV-tV  gr. 

Liquor  Stnjchnince  Hydrochloridi  (B.  P.)     (1  per  cent.),  2-8  mins.. 

Injectio  Strychnince  Hypodermica  (B.  P.)  (0.75  per  cent,  of  the  hydrochloride), 
5-10  mins.  hj'pcdermically. 

The  extract  is  generally  prescribed  in  pill  form,  while  strychnine  nitrate 
or  hydrochloride  may  be  given  in  solution,  pill  or  tablet;  where  rapid  action 
is  desired,  it  is  injected  subcutaneously.  A  number  of  unnecessary  preparations 
containing  strychnine  and  iron  and  quinine  are  contained  in  the  pharmacopoeias, 
which  also  mention  a  fluid-extract  (U.  S.  P.,  1  per  cent.),  and  a  liquid  extract 
(B.  P.,  1.5  per  cent.). 

Therapeutic  Uses. — Strychnine  is  used  largely  for  its  local  action  on 
the  digestive  organs  as  a  stomachic  bitter,  and  is  generally  prescribed 
in  the  form  of  the  tincture  or  the  extract  for  this  purpose,  as  in  this 
way  it  is  less  rapidly  absorbed  .than  when  given  as  an  alkaloidal  salt. 
It  may  be  combined  with  the  cinchona  preparation  or  with  one  of  the 
simple  bitters. 

Small  quantities  of  strychnine  are  of  benefit  in  many  ill-defined 
conditions  of  weakness,  cacliexia,  and  "want  of  tone"  generally.  The 
results  are  probably  partly  due  to  its  stomachic  effects  in  increasing 
appetite  and  digestion,  but  the  action  on  the  central  nervous  system 
cannot  be  overlooked.  The  slight  increase  in  the  irritability  of  the 
cord  probably  leads  to  an  improvement  in  almost  all  of  the  nutritive 
functions  through  increasing  the  contraction  of  the  vessels  and  pro- 
ducing greater  activity  of  the  muscles.  In  this  way  strychnine  per- 
haps deserves  the  name  of  "tonic"  more  than  most  of  the  drugs  to 
which  it  is  applied. 

As  a  stimulant  to  the  central  nervous  "system  strychnine  has  found 
wide  application  in  almost  every  form  of  paralysis,  and  as  long  as  dis- 
tinct anatomical  lesions  of  the  central  nervous  axis  are  absent,  it  may 
be  of  benefit;  for  instance,  it  is  often  valuable  in  lead  poisoning;  but 
where  the  continuity  of  the  axis  is  broken  by  hjvniorrhage  or  by  the 
destruction  of  the  nerve  cells,  little  improvement  is  to  be  anticipated 
from  its  use,  though  it  may  serve  to  delay  or  prevent  the  atrophy  of 
peripheral  nerves  and  muscles  in  some  of  these  cases.       When  the 


276  SUBSTANCES  ACTING  AFTER  ABSORPTION 

paralysis  is  due  to  an  inflammatory  process,  strychnine  is  to  be  used 
with  the  greatest  care,  or  is  perhaps  better  avoided  entirely  as  long 
as  the  irritation  is  present,  as  it  seems  to  increase  and  prolong  the 
inflammation  when  used  early  in  these  cases.  The  other  central  nervous 
stimulants,  such  as  caffeine  or  atropine,  have  not  been  employed  in  these 
forms  of  jiaralysis. 

Strychnine  is  used  as  a  respiratory  stimulant  in  some  forms  of  pul- 
monary disease  in  which  it  is  desirable  to  increase  the  respiration  or 
to  provoke  coughing.  It  has  been  advised  in  failure  of  the  respiration 
during  anaesthesia,  and  is  certainly  more  likely  to  be  beneficial  than 
the  great  majority  of  drugs  suggested  for  this  purpose.  Too  large 
doses  nuist  not  be  injected  in  these  cases,  however,  as  strychnine 
paralyzes  the  respiratory  centre  itself  when  given  in  excess.  In  other 
forms  of  poisoning  in  which  the  respiratory  centre  seems  in  danger, 
and  in  shock,  strychnine  may  also  be  of  service,  especially  when  it  is 
injcctetl  hypodermically.  Other  respiratory  stimulants  which  may  be 
substituted  for  strychnine  for  these  purposes  are  caffeine  and  atropine. 

In  amaurosis  or  amblyopia  unassociated  with  atrophy  of  the  optic 
nerve,  and  even  in  commencing  atrophy,  strychnine  has  frequently 
improved  the  vision.  In  many  cases  it  fails  to  produce  any  benefit, 
and  the  exact  conditions  in  which  improvement  can  be  looked  for  are 
unknown. 

Strychnine  has  been  used  in  heart  disease,  but  all  exact  observations 
agree  that  it  has  no  beneficial  action  (Parkinson  and  Rowlands).  In 
weakness  of  the  circulation  from  inefficiency  of  the  vasomotor  centre 
it  may  act,  though  Crile  denies  it  any  value  in  the  treatment  of  the 
low  blood-pressure  of  shock,  and  Cabot  could  not  find  any  change  in  the 
blood-pressure  after  its  use  in  a  number  of  conditions  in  which  it  is 
ordinarily  advised.  Cook  and  Briggs  found  the  blood-pressure  increased 
in  certain  cases  of  vasomotor  paresis,  howe^'er,  when  e^o-j^fr  S^-  ^^ 
strychnine  was  injected  hypodermically.  In  rare  cases  this  weakness 
of  the  medullary  centre  simulates  heart  disease,  and  this  may  account 
for  the  belief  in  the  virtues  of  strychnine  as  a  cardiac  tonic. 

Strychnine  is  said  to  l)e  of  value  in  chronic  alcoholism  in  lessening 
the  (lci)ression  which  forms  one  of  the  chief  difficulties  in  the  treatment. 

Poisoning. — In  cases  of  strychnine  poisoning,  the  first  treatment 
consists  in  the  evacuation  of  the  stomach  by  means  of  emetics,  or, 
better,  by  the  stomach  tube;  it  may  be  necessary  to  give  chloroform,  as 
the  atteni])t  to  pass  the  tube  is  often  followed  by  violent  convulsions. 
i*reparations  of  tannic  acid,  such  as  strong  tea,  may  be  given  in  order 
to  form  the  insoluble  tannate,  which,  however,  nuist  be  removed  as 
quickly  as  possible,  as  it  is  broken  up  by  the  acid  gastric  juice  and 
the  strychnine  is  rapidly  absorbed.  To  combat  the  convulsions,  depres- 
sants to  the  central  nervous  sxstem  should  be  given,  and,  although 
chloral  is  usuali.x  adxised,  chloroform  or  ether  is  often  preferable. 
It  is  unnecessary  to  ])ro(luce  deep  anaesthesia,  a  \'vw  whifi's  of  chloro- 
form being  often  suflicient  to  allay  the  convulsions.  The  advantage 
of  the  antcsthetics  over  chloral  is  that  thev  can  be  removed   if  anv 


PICROTOXIN  277 

symptoms  of  strychnine  paralysis  appear.  Opium  has  been  suggested, 
but  is  not  nearly  so  efficacious  in  strychnine  poisoning  as  members 
of  the  methane  series.  If  the  paralysis  comes  on,  artificial  respiration 
may  be  attempted,  although  the  poison  is  excreted  too  slowly  from  the 
organism  to  permit  of  much  hope  of  recovery. 


Bibliography. 

Pouhson.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxvi,  p.  22. 
Igersheimer.     Ibid.,  liv,  p.  73. 

Harnack.     Arch.  f.  exp.  Path.  u.  Pharm.,  xUx,  p.  157. 
Delezenne.     Arch,  de  Physiol.  (5),  vi,  p.  899. 
Houghton  and  Muirhead.     Medical  News,  1895,  i,  p.  612. 

Ryan,  McGuigan,  and  Becht.     Journ.  of  Pharm.  and  Exp.  Ther.,  ii,  p.  319;  v,  p.  469. 
Barenne.     Folia  neurobiologica,  iv,  p.  467;    v,  p.  42;   vi,  p.  277. 
Tiedemann.     Ztschr.  f.  allg.  Phys.,  xi,  p.  183. 
Mays.     Journal  of  Phys.,  viii,  p.  391. 

Filehne  and  his  pupils.     Pfluger's  Archiv,  Ixxxiii,  pp.  369,  397,  403. 
Singer.     Arch.  f.  Ophthalmologie,  1,  p.  665. 
Osterwald.     Arch.  f.  6xp.  Path.,  xliv,  p.  451. 

Venvorn  and  Baglioni.     Arch.  f.  [Anat.  u.]  Phys.,  1900,  p.  385,   Supplement,  pp.  152, 
193.     Ztschr.  f.  allg.  Physiol.,  ii,  p.  556,  iv,  p.  113. 

Meltzer,  Sala7it,  and  Gies.     Journ.  of  Exp.  Med.,  vi,  p.  107;    Amer.  Journ.  of  Phys.,  ix. 

Sherrington.     Proc.  Royal  Society,  Ixxvi,  B,  p.  287;    Journ.  of  Phys.,  xliii,  p.  232. 

Bayliss.     Ibid.,  Ixxx,  p.  353.  , 

Hale.     Journ.  of  Pharmacology,  i,  p.  39. 

Parkinson  and  Rowlands.     Quart.  Jour,  of  Mod.,  vii,  p.  42. 

In  addition,  strychnine  was  studied  by  Magendie,  CI.  Bernard,  and  Orfila. 


VI.     PICROTOXIN. 

Picrotoxin  is  the  best  known  member  of  a  group  of  convulsive  poisons, 
which  resemble  each  other  very  closel\'  in  action,  but  of  whose  chemistry 
little  is  known  beyond  the  fact  that  they  are  devoid  of  nitrogen.  It  is 
obtained  from  the  Anamirta  paniculata  (Anamirta  cocculus,  Menis- 
permum  cocculus),  and  is  a  neutral  indifferent  body.  Picrotoxin 
(C30H34O13)  may  be  broken  up  into  picrotoxinin  (CisHieOe),  which 
resembles  it  in  its  effects  on  animals,  and  picrotin  (C15H18O7),  which 
is  inactive. 

Other  poisons  resembling  picrotoxin  are  Cicutoxin,  derived  from  the  Cicuta 
virosa,  or  water  hemlock,  and  probably  from  other  species  of  Cicuta,  CEnan- 
thotoxin,  the  active  principle  of  (Enanthe  crocata,  water  dropwort,  or  dead 
tongue,  and  Coriamyrtin,  which  occurs  in  several  species  of  Conaria,  of  which 
the  best  known  is  the  Coriaria  myrtifolia  or  currier's  sumach.  Tidin,  the 
active  principle  of  the  toot  or  tutu  poison  of  New  Zealand,  is  obtained  from  other 
species  of  coriaria;  some  of  these  bodies  are  glucocides.  Camphor  and  some 
other  volatile  oil  derivatives,  notably  the  Thujon  of  al^sinthe  also  resemble 
picrotoxin  in  their  effects,  and  the  same  is  true  of  two  alkaloids  Samandanne 
and  Samandaridine  isolated  by  Faust  from  the  skin  of  the  newt.  Lastly,_  a 
number  of  the  members  of  the  digitalis  series  may  be  decomposed  into  bodies 
which,  devoid  of  the  characteristic  cardiac  action  of  digitalis,  produce  the 
same  symptoms  as  picrotoxin.  Among  these  may  be  mentioned  Toxiresin, 
obtained  from  digitoxin,  Digitaliresin  from  digitalin,  and  Oleandresin  from 
oleandrin. 


27S  SUBSTANCES  ACTING  AFTER  ABSORPTION 

Symptoms. — The  symptoms,  wliich  are  often  somewhat  late  in 
;(l)p(■;lrin,<,^  are  very  shnilar  in  all  classes  of  vertebrates.  In  man  vomit- 
ing is  not  infrequently  ol)serve(l  after  members  of  this  series,  or  the 
first  symptoms  may  be  salivation,  acceleration  of  the  respiration,  and 
some  slowness  of  the  pnlse  and  palpitation  of  the  heart.  A  condition 
of  stupor  and  unconsciousness  follows  and  then  a  series  of  powerful 
convulsions,  which,  commencing  in  tonic  spasms,  soon  change  to  clonic 
movements  of  the  limbs  and  jaws.  The  respiration  is  interrupted 
during  these  spasms,  but  is  reinstated  during  the  intervals  of  c^uiet 
and  collapse  which  follow  them.  The  convulsions  return  after  a  short 
pause,  and  this  alteration  of  spasm  and  quiet  may  continue  for  some 
time,  although  the  respiration  often  fails  to  return  after  one  of  the 
spasms,  and  fatal  asphyxia  results. 

Similar  effects  are  observed  in  the  lower  mammals.  After  a  pre- 
liminary stage  in  which  twitching  of  the  muscles  and  vomiting  often 
occur,  and  in  which  the  respiration  is  accelerated,  while  the  pulse  is 
slow,  a  violent  emprosthotonic  convulsion  sets  in,  but  soon  changes 
to  clonic  movements;  these  may  last  for  some  time,  but  eventually 
become  weaker  and  give  place  to  a  condition  of  quiet  and  depression. 
An  increase  in  the  reflex  excitability  is  noticeable  during  this  interval, 
the  animal  is  easily  startled  and  occasional  twitching  of  the  muscles 
may  be  observed.  Very  soon  a  second  convulsion  sets  in,  and  this 
may  be  fatal  from  asphyxia,  but  the  symptoms  often  continue  for  an 
hour  or  more,  violent  spasms  alternating  with  periods  of  depression 
and  collapse.  In  the  frog  clonic  convulsions  are  also  the  chief  feature 
of  the  intoxication.  Very  often  the  animal  becomes  distended  with  air 
during  the  convulsions,  and  gives  a  curious  cry  in  releasing  it.  The 
heart  is  always  slowed  and  may  cease  to  beat  altogether  for  a 
time. 

Action. — The  clonic  convulsions  of  picrotoxin  poisoning  are  altogether 
difierent  from  those  of  strychnine  and  other  similar  bodies,  which 
induce  prolonged  tonic  convulsions,  and  it  was  early  surmised  that  the 
members  of  this  series  act  on  a  different  part  of  the  Central  Nervous 
System.  In  the  fish  convulsions  arise  from  picrotoxin  after  all  the 
ner\'ous  system  has  been  removed  except  the  spinal  cord.  In  the  frog 
they  persist  after  the  cerebrum  has  been  destroyed,  and  even  when  all 
of  the  brain  above  the  medulla  oblongata  has  been  removed,  although 
they  are  weakened  by  the  destruction  of  the  optic  lobes;  on  the  other 
hand,  they  disappear,  or  at  any  rate  lose  their  typical  character  when 
the  medulla  oblongata  is  removed.  In  mannnals,  the  convulsions  are 
less  typical  when  the  cerebral  hemispheres  are  removed  and  disappear 
when  the  pons  is  destroyed.  The  seat  of  action  thus  seems  to  move 
upward  as  the  higher  parts  of  the  central  nervous  system  become  more 
developed,  the  chief  effects  arising  from  the  spinal  cord  and  medulla 
and  optic  lobes  in  the  frog  and  from  the  cerebrum  and  mid-brain  in 
mannnals.  It  is  possible  that  in  man  the  cerebrum  is  even  more  involved 
in  the  action  than  in  the  lower  mammals.  In  Toot  i)oisoning  in  man, 
it    is    often    obser\'ed    that    a    confused    mental    c-ondition    is  present 


PICROTOXIN  279 

and  that  the  memory  is  impaired  after  the  attack  and  even  for  some 
days  later. 

The'  stimuhition  of  the  medulhi  is  seen  in  the  acceleration  of  the 
respiration,  in  the  slow  pulse,  which  is  due  to  inhibitory  action,  in  a  very 
marked  rise  of  the  blood-pressure,  and  in  the  vomiting  and  salivation. 
In  many  animals  the  reflexes  are  found  to  be  increased  when  the 
medulla  is  severed  from  the  cord,  and  this  indicates  that  the  spinal 
cord  is  also  more  excitable  than  normally.  Griinwald  suggests  that 
the  centres  controlling  the  cranial  and  sacral  autonomic  nerves  are 
especially  susceptible  to  the  action  of  these  poisons. 

The  Heart  is  rendered  slow  by  picrotoxin;  this  is  due  principally  to 
stimulation  of  the  inhibitory  centre  in  the  medulla,  since  on  division 
of  the  vagi  the  heart  returns  to  almost  its  normal  rate.  Some  direct 
depression  of  the  heart  is  observed  after  large  doses  in  the  frog.  Picro- 
toxin causes  a  very  marked  rise  in  the  arterial  tension  from  stimulation 
of  the  vaso-constrictor  centres  in  the  medulla  and  upper  part  of  the 
cord. 

The  Respiration  is  accelerated  before  any  convulsions  set  in,  and 
in  the  intervals  between  the  spasms  it  is  also  very  rapid,  owing  to 
the  action  on  the  centre.  Late  in  the  intoxication  the  breathing 
may  become  slow  and  labored,  probably  from  approaching  central 
paralysis. 

The  Vomiting  often  observed  in  man  and  the  dog  under  picrotoxin 
is  probably  of  central  origin  and  not  due  to  gastric  irritation. 

The  peripheral  Nerves  and  Muscles  do  not  seem  to  be  affected  by 
these  poisons. 

The  fate  of  picrotoxin  in  the  body  and  the  way  in  which  it  is 
excreted  are  unknown.  Like  other  convulsive  poisons,  it  tends  to 
lower  the  temperature  when  it  is  given  in  quantities  insufficient  to 
cause  convulsions. 

The  convulsions  of  picrotoxin  and  its  allies  disappear  when  chloro- 
form or  chloral  is  administered.  On  the  other  hand,  the  respiration, 
weakened  by  narcotic  poisons  such  as  chloral,  is  accelerated  by  picro- 
toxin, the  blood-pressure  rises,  and  the  sleep  is  less  prolonged.  Animals 
are  not  awakened  at  once  from  narcosis  by  picrotoxin,  but  coriamyrtin 
has  this  effect. 

Picrotoxin  is  not  antidotal  in  morphine  poisoning  in  animals,  but 
may  possibly  be  so  in  man. 

Therapeutic  Uses. — Picrotoxin  has  been  used  as  an  ointment  to 
destroy  pediculi,  and  in  some  forms  of  skin  disease,  but  is  too  poisonous 
to  be  recommended  for  this  purpose.  It  has  been  proposed  to  give  it 
by  subcutaneous  injection  in  cases  of  collapse  and  in  narcotic  poisoning, 
but  it  has  not  been  employed  for  this  purpose  in  therapeutics  as  yet. 
It  has  some  reputation  in  the  profuse  night-sweats  of  phthisis,  which 
it  diminishes  in  a  certain  proportion  of  cases,  probably  by  increasing 
the  respiration  and  thus  preventing  the  stimulation  of  the  nervous 
mechanism  of  perspiration  through  the  partial  asphyxia.  Dose,  6V~20 
gr.  in  pill  or  tablet. 


280  SUBSTANCES  ACTING  AFTER  ABSORPTION 

BiBLIOGRAI'IIV. 

Luchsinger.     Pfliigcr's  Arch.,  xvi,  p.  530. 

Marshall.  Trans.  Royal  Soc.  Edinburgh,  xlvii  (ii),  p.  287  (Toot  plant);  Journ.  of 
Pharm.  and  Exp.  Ther.,  iv,  p.  135  (coriamyrtin). 

Koppen.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxix,  p.  327. 

Gottlieb.     Ibid.,  xxx,  p.  21. 

Harnack.     Ztsch.  f.  klin.  Med.,  xxv,  p.  16. 

Pohl.     Arch.  f.  exp.  Path.,  xxxiv,  p.  259.    (Cicutoxin  and  CEnanthotoxin.) 

Perrier.     Ibid.,  iv,  p.  191.     (Toxiresin,  digitaliresin,  etc.) 

Faust.     Ibid.,  xli,  p.  299;    xhii,  p.  84.     (Samandarin.) 

Fitcliett  and  Malcolm.     Quart.  Journ.  Exp.  Phys,  ii,  p.  335. 

Griinwald.     Arch.  f.  exp.  Path.  u.  Pharm.,  Ix,  p.  249. 

Vn.    CAFFEINE. 

In  a  number  of  plants  used  in  different  parts  of  the  world  to  form 
beverages  and  condiments,  there  are  found  the  xanthine  compounds, 
Caffeine,  Theobromine  and  TheoyhyUine  (TJieocine),  which  have  been 
employed  in  therapeutics  of  late  years,  and  have,  therefore,  acquired 
a  double  importance  as  drugs  and  as  articles  of  diet.  The  wide- 
spread use  of  preparations  of  these  by  uncivilized  peoples  is  a  curious 
and  unexplained  fact,  especially  as  they  possess  neither  peculiar  taste 
nor  odor  to  guide  in  the  selection  of  the  plants  in  which  they  exist. 
Besides,  caffeine  and  its  allies  in  moderate  quantities  induce  no  marked 
symptoms,  such  as  follow  the  use  of  alcohol,  opium  or  hashish  and 
explain  their  use  among  widely  separated  peoples.  On  the  contrary, 
the  only  effects  to  be  observed  are  a  brightening  of  the  intellectual 
faculties  and  an  increased  capacity  for  mental  and  physical  work. 
Coffee,  the  use  of  which  is  derived  from  the  Arabians,  is  the  berry  of 
Coffea  Arabica  and  contains  caffeine ;  tea,  the  leaves  of  Thea  Chinensis, 
contains  caffeine  along  with  theophylline.  Cacao,  cocoa,  or  chocolate 
is  derived  from  the  seeds  of  Theobroma  cacao,  a  tree  indigenous  in 
Brazil  and  Central  America  and  contains  theobromine.  In  central 
Africa,  the  Cola  or  Kola  nut  (Sterculia  acuminata)  is  used  by  the 
natives,  and  contains  caffeine  with  small  quantities  of  theobromine. 
In  Brazil,  Guarana  paste  is  formed  from  the  seeds  of  Paullinia  sor- 
bilis,  and  contains  caffeine  and  theobromine,  while  in  the  Argentine 
Republic,  Yerba  Mate  or  Paraguay  tea  (Ilex  Paraguayensis)  is  used  to 
form  a  beverage  which  contains  a  small  quantity  of  caffeine.  Another 
species  of  Ilex  is  met  with  in  Virginia  and  Carolina  under  the  name  of 
Apalache  tea  or  Youpon,  and  also  contains  caffeine. 

These  three  principles,  caffeine,  theobromine  and  tlico])liylliiu'.  are 
|)iiriiie  derivatives  closely  related  to  the  xanthine  bodies  found  in  the 
urine  and  tissues  of  the  animals;  theobromine  and  tlu'oi)liyllin  are 
dimethylxanthine  and  caffeine  is  trimethylxanthine. 

XaJithin,c  Theobromine 

''NH— C— N    .     '  CH3N— C— N  ■ 


r/ 


CH 


C:0     C— NH<\  CO     C— NCH3p. 

11^  II  ^\ 

UN— CO>s  '  Nli— CO  .  Th(!()pliyllin3  ,>>  .Caffeine 

CHaN— C— N\.  'CHsNJ^C— N'A     .     V 

I    <ll  ^tH  I       II  Vll 

•V  CO  ^C— NH/  -     CO      C— NCH3/ 

I        I  ^  I        I        -A 

ClhN-rCO  CHsN— CO 


^•^ 


«to 


CAFFEINE  281 

Action, — These  all  resemble  Ccach  other  in  most  points  of  their  phar- 
macological action,  although  caffeine  acts  on  the  central  nervous  sN'stem 
as  well  as  on  the  kidneys,  muscle  and  heart,  while  theobromine  has 
comparatively  little  effect  except  on  the  last  three. 

Central  Nervous  System. — In  man,  caffeine  stimulates  the  central 
nervous  system,  in  particular  that  part  associated  with  the  psychical 
functions.'  The  ideas  become  clearer,  thought  flows  more  easily  and 
rapidly,  and  fatigue  and  drowsiness  disappear.  Not  infrequently,  how- 
ever, connected  thought  is  rendered  more  difficult,  for  impressions 
follow  each  other  so  rapidly  that  the  attention  is  distracted,  and  it 
requires  more  and  more  effort  to  limit  it  to  a  single  oJDJect.  If  the 
quantity  ingested  is  small,  however,  the  results  are  of  distinct  benefit 
in  inteliectual  work.  The  capacity  for  physical  exertion  is  also  aug- 
mented, as  has  been  demonstrated  repeatedly  by  soldiers  on  the  march, 
and  more  recently  by  more  exact  experiments  with  the  ergograph.  The 
stimulation  of  the  higher  nervous  centres  is  often  manifested  in  the 
insomnia  and  restlessness  which  in  many  people  follow  indulgence  in 
coffee  or  tea  late  at  night.  Kraepelin  has  investigated  the  eft'ects  of 
caffeine  from  the  psychological  point  of  view,  and  finds  that  both  tea 
and  coffee  facilitate  the  reception  of  sensory  impressions  and  also  the 
association  of  ideas,  especially  in  fatigue,  while  the  transformation  of 
intellectual  conceptions  into  actual  movements  is  retarded.  This  he 
regards  as  due  to  stimulation  of  the  highest  or  controlling  functions 
of  the  brain,  caffeine  acting  on  the  same  parts  as  are  first  affected  by 
alcohol  and  the  methane  derivatives,  but  altering  them  in  the  opposite 
direction.  The  effect  of  caffeine  on  the  acuteness  of  the  senses  has 
been  demonstrated  by  the  greater  accuracy  of  touch  under  its  influence. 

Large  quantities  of  caffeine  often  cause  headache  and  some  confusion, 
and  in  rare  cases  of  special  susceptibility  a  mild  form  of  delirium  may 
be  elicited,  or  noises  in  the  ears  and  flashes  of  light  may  indicate  derange- 
ment of  the  special  senses.  The  pulse  is  quickened,  and  occasionally 
palpitation  and  uneasiness  in  the  region  of  the  heart  are  complained  of. 
Convulsive  movements  of  the  muscles  of  the  hand,  and  tremor  in 
different  parts  of  the  body  have  also  been  recorded  in  some  cases. 
These  effects  are  induced  only  with  difficulty  in  habitual  drinkers  of 
tea  or  coffee,  so  that  the  continued  administration  of  small  quantities 
of  caffeine  evidently  gives  rise  to  tolerance. 

In  the  lower  mammals  the  injection  of  large  ciuantities  of  caffeine  is 
followed  by  symptoms  closely  resembling  those  induced  by  strychnine. 
The  reflex 'irritability  is  remarkably  increased,  the  lightest  touch  being 
followed  by  powerful  contraction  of  almost  all  the  muscles  of  the  body. 
After  a  time  these  contractions  occur  without  any  apparent  stimulus, 
and  culminate  in  tonic  convulsions  which  last  for  several  seconds. 
During  these,  the  respiration  ceases  because  the  respiratory  muscles  are 
involved  in  the  spasm,  and  accasionally  it  fails  to  be  reinstated  when 
the  convulsions  pass  off.  In  other  instances  the  spasms  become  weaker 
and  occur  at  longer  intervals;  the  respiration  diminishes  in  freciiiency 
and  depth  and  eventually  ceases. 


282 


SUBSTANCES  ACTING  AFTER  ABSORPTION 


The  syinptonis  induced  In'  caffeine  in  tlie  lower  mammals  are  due 
for  the  most  part  to  its  acting  on  the  spinal  cord  in  the  same  way  as 
strychnine,  though  small  doses  may  act  on  the  brain,  for  they  often 
elicit  restlessness  and  timidity  without  any  marked  change  in  the  reflex 
excitahility.  The  centres  in  the  medulla  oblongata  are  also  involved 
in  the  effects,  as  is  indicated  by  acceleration  of  the  breathing  and  occa- 
sionally by  some  slowness  of  the  pulse  from  action  on  the  pneumogastric 
centre. 

Frogs  show  no  nervous  symptoms  that  cannot  be  ascribed  to  action 
on  the  spinal  cord,  and  in  some  species  these  are  elicited  with  con- 
sitlerable  difficulty  owing  to  the  muscular  action  described  below. 

On  comparing  the  effects  of  caffeine  and  strychnine  on  the  central 
nervous  system,  it  will  be  found  that  while  there  is  a  general  similarity 
in  their  action,  the  latter  causes  more  marked  stimulation  of  the  lower 
divisions  and  has  less  action  on  the  cerebrum  in  mammals  and  man. 
They  both  produce  a  general  increase  in  the  activity  of  nerve  cells, 
but  caffeine  acts  more  on  the  psychical,  strychnine  more  on  the  reflex 
functions. 

Fig.  19 


I 

1 


A  muscular  fibre  of  tlie  frog  (highly  magnified).     -1,  normal;    B,  after  the   application 
of  caffeine  solution.     The  coarse  striiB  in  B  are  the  folds  of  the  sarcolemma. 


Theophylline  resembles  caffeine  in  its  action  on  the  central  nervous 
system,  while  theobromine  induces  few  or  no  symptoms  of  stimulation. 
The  monomethyl-xanthines  and  xanthine  itself  stimulate  the  central 
nervous  system  in  the  frog  (Schmiedeberg). 

The  Muscular  action  of  caffeine  is  best  seen  in  the  Hana  temj)oraria 
(grass  frogj,  although  it  is  also  induced  in  other  sj)ecies  of  frogs,  and 
some  rigidity  may  be  elicited  in  mammals  by  very  large  doses.  ^Vhen 
a  few  drops  of  caffeine  are  injected  into  the  leg  of  a  frog  there  follows 
a  peculiar  stiffness  and  hardness  in  the  muscles  around  the  point  of 
injection,  which  slowly  sj^reads  to  other  ])arts  of  the  body  and  induces 
the  appearance  of  rigor  mortis.  The  same  effect  is  observed  when 
teased  muscle  fibres  are  subjected  to  a  caffeine  solution  under  a  high- 
power  microscope.  The  fibres  contract,  become  white  and  oj^aque,  and 
look  stiff  and  inflexible;  the  transverse  stria*  disa])i)car,  while  the  longi- 
tudinal   bcconic   inor(^   easily    visible    (Fig.    H)).      This   appearance    is 


CAFFEINE  283 

(hie  to  the  death  aiul  rij;or  mortis  of  tlie  fibres,  in  which  the  inyogeii  is 
formed  into  myogen-fibrin  apparently-;  the  same  change  occnrs  when 
caffeine  is  added  to  niNogcn  in  the  test-tube. 

In  small  (luantities  caffeine  increases  the  irritability  of  muscle  as 
well  as  its  absolute  strength  and  extensibility;  that  is,  the  nniscle  con- 
tracts on  a  weaker  stimulus  and  against  a  greater  load  than  it  does 
normally.  The  amount  of  work  done  before  fatigue  sets  in  is  also 
increased,  unless  when  large  quantities  are  applied,  when  the  capacity 
for  work  is  lessened;  and  with  the  first  appearance  of  rigor  it  ceases 
to  react  to  stimuli  altogether.  Sobieranski  has  recently  shown  that  in 
ordinary  doses  caffeine  increases  the  work  done  by  the  human  muscles 
when  tiiey  are  stimulated  by  electric  shocks.  The  universally  recog- 
nized effect  of  tea  and  coffee  in  increasing  the  capacity  for  physical 
work  and  in  relieving  fatigue  has  generally  been  regarded  as  due  to 
changes  in  the  nerve  cells,  but  the  peripheral  action  on  the  muscle  may 
also  play  a  part  in  it.  While  the  action  of  theobromine  on  the  central 
nervous  system  is  much  less  marked  than  that  of  caffeine,  muscle  enters 
into  rigor  after  the  former  more  readily,  and  xanthine  exceeds  even 
theobromine  in  its  power  to  produce  this  change. 

Circulation. — In  man,  ordinary  doses  of  caffeine  often  induce  some 
slowing  of  the  pulse,  which  apparently  arises  from  a  mild  stimulation 
of  the  inhibitory  centre  in  the  medulla ;  but  not  infrequently  no  altera- 
tion in  the  pulse  rate  is  observable.  The  blood-pressure  does  not  appear 
to  be  materially  altered  by  caffeine,  a  slight  rise  of  5-10  mm.  occurring 
in  individuals,  but  not  very  frequently.  Sometimes  palpitation  is 
complained  of  in  excessive  tea  and  coffee  drinkers,  and  this  may  perhaps 
indicate  stronger  action  of  the  inhibitory  centres,  but  may  equally-  well 
be  attributed  to  gastric  disturbance.  The  effects  of  therapeutic  doses 
of  caffeine  on  the  circulation  in  man  are  quite  insignificant. 

When  caffeine  is  injected  in  large  quantities  intravenously  in  animals, 
the  heart  is  accelerated  considerably  without  any  significant  change 
in  the  extent  of  systole  and  diastole.  The  acceleration  is  not  dependent 
on  changes  in  the  regulating  nerves  of  the  heart,  but  arises  from  a  direct 
stimulating  action  on  the  cardiac  muscle,  and  especially  on  that  part 
from  which  the  rhythm  originates.  Vagus  stimulation  has  less  effect 
than  usual,  but  this  is  due  to  increased  irritability  of  the  heart  and  not 
to  partial  paralysis  of  the  nerve  ends.  A  similar  acceleration  is  induced 
by  caffeine  after  division  of  both  accelerator  and  vagus  nerves  and  after 
the  paralysis  of  the  inhibitory  terminations  by  atropine.  Still  larger 
quantities  of  caffeine  injected  intravenously  in  mammals  cause  weakness 
and  irregularity  of  the  heart.  The  quantities  used  in  therapeutics  in 
man  seem  insufficient  to  induce  either  the  acceleration  or  the  subsequent 
irregularity  observed  in  animals.  The  acceleration  of  the  heart  is  not 
always  accompanied  by  an  increase  in  the  amount  expelled  per  minute 
(Bock),  for  the  contractions  may  follow  each  other  so  quickly  that  there 
is  not  sufficient  interval  for  the  inflow  of  blood. 

The  blood-pressure  under  these  large  intravenous  injections  in  animals 
often  rises  to  some  extent,  but  not  infrequently-  shows  little  alteration, 


284  SUBSTANCES  ACTING  AFTER  ABSORPTION 

and  the  increase  in  the  hlood-pressnre  is  rarely  significant.  Caffeine 
tends  to  stimnlate  the  vasomotor  centre  in  the  medulla,  and  this  would 
raise  the  lijood-pressure,  were  it  not  for  a  sinniltancoiis  widening  of  the 
vessels  through  a  direct  action  on  the  walls;  this  neutralizes  in  large 
part  the  central  action  on  the  circulation,  so  that  the  blood-pressure 
shows  only  slight  changes  (Sollmann  and  Pilcher).  When  very  large 
quantities  weaken  the  heart,  the  blood-pressure  falls  to  a  considerable 
extent,  but  if  convulsions  supervene  it  may  again  rise. 

The  direct  dilator  eff"ect  of  caft'eine  has  sometimes  been  observed 
in  the  coronary  vessels  of  the  heart,  and  has  led  to  the  use  of  caffeine 
in  conditions  in  which  narrowing  of  these  vessels  is  diagnosed.  There 
is  no  reason  to  suppose  that  the  quantities  used  in  therapeutics  have 
any  effect  whatever  on  the  vessels.  Theobromine  and  xanthine  have 
an  action  on  the  heart  and  vessels  similar  to  that  of  caft'eine. 


Respiration  of  a  rabbit  which  had  been  slowed  by  morphine.  At  C,  catfeine  was  in- 
jected intravenously  and  the  respiration  was  at  once  greatly  accelerated  and  moved 
toward  the  inspiratory  position. 

In  the  frog's  heart,  caffeine  in  small  quantities  accelerates  and 
strengthens  the  beat  for  a  short  time,  while  larger  amounts  slow  the 
beat  and  lessen  the  relaxation  of  the  heart,  which  finally  passes  into 
rigor  resembling  that  seen  in  the  skeletal  muscles. 

The  Respiration  is  quickened  by  caffeine,  owing  to  a  stimulant  action 
on  the  medullary  centre.  This  is  seen  in  the  imi)rovemont  of  the 
respiration  in  cases  of  dangerous  i)oisoning  with  alcohol,  opium  and 
other  drugs  which  ])rove  fatal  by  depressing  the  centre,  but  is  much  less 
marked  in  normal  animals.  The  quicker  resi)iration  is  often  more 
shallow  than  before  the  administration  of  calVelne,  but  the  total  air 
breathed  is  increased  and  the  blood  is  better  aerated;  the  lessened  con- 
tent of  carbon  dioxide  in  the  blood  causes  the  breathing  to  be  shallower 
throngh  lessening  the  stimulus  to  the  respiratory  centre.  The  action 
of  caiVeinc  on  the  centre  is  thus  diametricnily  opposed  to  tluit  of  mor- 
phine. 


CAFFEINE 


285 


Fig.  21 


The  Temperature  has  been  found  to  be  raised  by  caft'ehie  through  its 
action  on  the  nervous  centres  and  perhaps  on  the  muscles.  The  increase 
is,  however,  comparatively  insignificant 
(0.5-1°  C.)  and  is  seen  only  in  cases  in 
which  an  almost  poisonous  dose  has  been 
used. 

The  Alimentary  Tract  is  not  affected  by 
caffeine,  l)ut  after  theobromine  discomfort 
and  loss  of  appetite  are  sometimes  com- 
plained of,  probably  owing  to  changes  in 
the  gastric  mucous  membrane.  These 
are  much  more  marked  after  even  small 
doses  of  theophylline,  and  small  hemor- 
rhages and  erosions  have  been  found  in  the 
stomach,  both  in  man  and  animals  (Allard). 

Kidney. — The  most  important  property 
of  caft'eine  from  a  therapeutic  point  of 
view  is  its  power  of  increasing  the  secre- 
tion of  urine.  It  is  an  everyday  experience 
that  strong  coffee  or  tea  increases  the 
urine  to  a  much  greater  extent  than  the 
same  amount  of  water,  and  this  has  been 
shown  to  be  due  to  the  caffeine  contained 
in  these  beverages.  Caffeine  injected 
intravenously  in  the  rabbit  has  a  similar 
diuretic  effect,  though  there  is  often  a 
short  preliminary  period  in  which  the 
secretion  is  actually  diminished;  this  is 
especially  marked  when  the  injection  is 
made  rapidly,  and  may  arise  from  cir- 
culatory changes  or  perhaps  from  the 
action  of  an  overwhelming  dose  in  the 
kidney  itself.  The  caffeine  diuresis  is 
accompanied  by  an  increase  in  the  volume 
of  the  kidney  which  may  be  registered  by 
the  oncometer,  and  which  in(%ates  that 
the  renal  vessels  undergo  dilatation  under 
the  drug.  Some  observers  have  attempted 
to  explain  the  increase  in  the  urine  as  due 
to  the  dilatation  of  the  vessels,  but  the 
general  view  is  that  this  dila,tation  is 
merely  the  accompaniment  of  the  aug- 
mented activity  of  the  kidney  and  not 
its  cause. 

Among  those  who  recognize  the  flirect 
action   on    the   kidney   as   the    cause  of 

the  increased  secretion,  a  further  divergence  of  opinion  is  met  with, 
one  party  holding  that  caffeine  lessens  the   reabsorption   in   the  cells 


Caffeine  diuresis  in  a  rabbit.  The 
amount  of  urine  passed  in  ten 
minutes  is  represented  by  the 
height  of  the  rectangles.  The  first 
of  these,  A-5,  represent  the  normal 
secretion.  At  5  a  small  dose,  and 
at  C  a  large  dose  of  caffeine  was 
injected  intravenously,  and  the 
secretion  is  accordingly  increased. 
The  shaded  part  of  the  rectangles 
represents  the  amount  of  solids  in 
the  urine.  It  will  be  noted  that 
these  are  increased  hut  not  in  the 
same  ratio  as  the  fluid.  The  dotted 
line  represents  the  average  height 
ol  the  blood-pressure  during  each 
period  of  ten  minutes. 


286  SUBSTANCES  ACTING  AFTER   ABSORPTION 

of  the  tubules  and  thus  permits  the  glomerular  secretion  to  reach 
the  ureters  in  larger  quantity  than  normally,  while  the  other  maintains 
that  caffeine  increases  the  activity  of  the  cells  of  the  tubules  and  thus 
adds  to  the  glomerular  secretion  more  than  usual.  The  question  can 
only  be  solved  when  the  physiology  of  the  kidney  is  determined  more 
satisfactorily;  the  experiments  of  Cullis  seem  to_  argue  in  favor  of  the 
latter  view,  for  in  the  frog  the  caffeine  diuresis  continues  after  the 
blood  supply  to  the  glomerulus  is  cut  off  so  that  only  the  secretion  of 
the  tubules  can  reach  the  ureters.  Barcroft  states  that  caffeine  increases 
the  metabolism  of  the  kidney  when  it  causes  diuresis,  and  subsequently 
depresses  it;  in  this  second  stage  such  diuretics  as  act  on  the  glomerulus 
only  continue  to  be  effective,  while  those  that  presumably  affect  the 
tubules  fail  to  increase  the  urine.  He  therefore  concludes  that  caffeine 
first  stimulates  the  secretion  of  the  renal  tubules  and  in  large  doses 
paralyzes  it.  On  the  other  hand,  other  observers  state  that  in  uranium 
poisoning  in  which  the  renal  tubules  are  primarily  affected,  caffeine 
continues  to  act  as  a  diuretic  as  long  as  urine  is  secreted,  which  suggests 
that  the  tubules  are  not  the  seat  of  action  of  caffeine. 

Caffeine  does  not  injure  the  kidney  even  when  it  is  given  in  large 
doses  and  for  prolonged  periods;  it  thus  differs  from  most  other  diuretics 
and  may  be  administered  in  renal  disorders  without  risk  of  increasing 
the  lesions. 

In  the  caft'eine  diuresis  the  fluid  part  of  the  urine  is  increased  chiefly, 
but  the  solids  also  undergo  an  augmentation,  though  not  to  the  same 
extent.  Among  the  solids  the  chief  increase  is  seen  in  the  sodium 
chloride,  the  nitrogenous  constituents  undergoing  less  alteration, 
although  they  also  rise  in  amount.  The  dilution  of  the  urine  reduces 
the  concentration  of  acid,  and  in  addition  the  alkali  of  the  blood  escapes 
through  the  kidney  in  larger  quantity,  so  that  the  urine  in  caffeine 
diuresis  is  more  nearly  neutral  and  is  less  irritant  to  the  urinary  passages 
than  normally.^ 

The  excretion  of  large  quantities  of  fluid  in  the  urine  is.  of  course, 
accompanied  by  a  diminution  of  the  fluids  of  the  blood,  but  the  latter 
soon  recuperates  itself  from  the  tissues.  If  there  is  any  accumulation 
of  liquid,  such  as  oedema,  it  is  drained  into  the  blood  to  replace  the 
fluid  thrown  out  by  the  kidney,  and  caffeine  may  accordingly  be  used 
to  remove  (rdema  or  dropsy  in  this  way.  If  no  such  accunndation. 
exists,  the  blood  draws  on  the  fluids  of  the  intestine  and  stomach,  and 
their  withdrawal  leads  to  the  sensation  of  thirst.  As  a  tliuretic,  caffeine 
is  distinctly  inferior  to  theobromine;  in  the  flrst  place,  because  the 
diuresis  is  less  certain  and  is  often  accompanied  by  nervous  syini)toms— 
sleeplessness  and  restl(>ssness;  and  secondly,  because  the  increase  in  the 
secretion  is  smaller  and  lasts  for  a  shorter  time.  Theophylline  is  said 
to  act  on  the  ki(lii<"\-  even  more  powerfully  than  theobromine. 

'  .\  small  aiiujuiit  of  suKur  is  oftrii  fuuml  in  tii<-  uriiu'  "f  i:il)l)its  after  I'alTeiiic,  and 
lliis  has  been  stated  to  arise  from  an  excess  of  sugar  in  tlie  l)lo(Mi;  this  liyperglyoa>niia 
apiH-ars  to  proceed  from  excessive  action  of  the  suprarenal  ghuuls  from  the  excitement 
in  rahbits,  and  has  no  clinical  significance  (Stenstrom). 


CAFFEINE  287 

Excretion. — Caffeine  is  excreted  in  the  urine  to  a  very  small  extent 
as  such.  During  its  passage  through  the  body  it  loses  its  methyl 
groups  and  first  becomes  dimethyl-  and  then  monomethylxanthine. 
Eventually  xanthine  is  formed  and  this  probably  breaks  up  into  urea. 
In  the  urine  are  found  small  quantities  of  the  unchanged  drug,  accom- 
panied by  larger  quantities  of  dimethylxanthine  and  monomenthylxan- 
thine.  After  theobromine  and  theophylline  some  of  the  unchanged 
drug  is  found  in  the  urine  along  with  monomethylxanthine.  The 
uric  acid  of  the  urine  is  not  increased  by  any  of  these  drugs. 

The  exact  order  in  which  the  methyl  groups  are  lost  in  the  tissues  appears 
to  differ  in  different  animals;  in  the  dog  all  three  isomeric  dimethylxanthines 
are  formed  from  caffeine  and  after  large  doses  appear  in  the  urine,  although 
theophylline  predominates,  while  m  the  rabbit  and  in  man  paraxanthine  is 
formed  in  larger  amounts.  The  monomethylxanthines  are  also  excreted  in 
different  proportions  in  different  animals,  heteroxanthine  prevailing  in  man 
and  the  rabbit. 

Tolerance. — A  certain  degree  of  tolerance  is  acquired  from  the  pro- 
longed use  of  coffee,  tea,  or  chocolate,  as  is  shown  by  the  absence  of 
diuresis.  Apparently  the  caffeine  and  its  allies  undergo  more  rapid 
destruction,  but  this  does  not  explain  the  tolerance  completely,  for 
even  after  prolonged  administration  large  quantities  of  these  bodies 
may  be  obtained  from  the  tissues,  which  must  have  ceased  to  react  to 
them,  as  well  a?  learning  to  destroy  them  more  rapidly  than  normally. 

Theobromine  resembles  caffeine  in  its  effects  except  that  it  has  little 
or  no  action  on  the  central  nervous  system.  It  is  esteemed  a  more 
powerful  diuretic  and  generally  has  no  other  effects  in  man.  When 
large  doses  are  taken  for  some  time,  it  tends  to  act  on  the  stomach, 
causing  loss  of  appetite  and  nausea. 

TheophyUine  or  Theocine  is  the  most  powerful  diuretic  of  the  group, 
but  in  a  number  of  cases  has  a  deleterious  action  on  the  stomach  and 
in  several  instances  epileptiform  convulsions  have  followed  its  use. 

Preparations. 

Caffeina  (U.  S.  p.,  B.  p.),  long,  white,  silky  crystals,  without  odor,  but 
posessing  a  bitter  taste,  but  little  soluble  m  cold  water,  more  so  in  alcohol, 
still  more  so  in  boiling  water.  0.065  G.  (1  gr.);  B.  P.,  1-5  grs.  Caffeme  is  best 
prescribed  either  in  powder  or  in  tablets.  It  may  also  be  giA-en  in  water  with 
saUcylate  of  sodium,  which  aids  its  solution.  The  two  foUo^nng  preparations 
are  unsatisfactory:  .    . 

Caffeina  Citraia  (U.  S.  P.),  Caffeince  Citras  (B.  P.),  a  white  powder  consisting 
of  a  weak  chemical  combination  of  citric  acid  and  caffeine.  It  is  decomposed 
by  mbcture  with  more  than  3  parts  of  water.    0.125  G.  (2  grs.);  B.  P.,  2-10  grs. 

Caffeina  Citraia  Effervescens  (U.  S.  P.),  Caffeirm  Citras  Effervescens  (B.  P.), 
a  mixture  of  citrated  caffeine  with  sodium  bicarbonate,  tartaric  and  citric  acids. 
On  throwing  the  powder  m  water  it  effervesces,  owing  to  the  acids  acting  on 
the  bicarbonate  and  liberating  carbonic  acid.  This  preparation  contains  only 
2  per  cent,  of  caffeme.    Dose,  4  G.  (60 grs.);  B^ P.,  60-120  grs. 

Theobromina  (unofficial)  is  a  crystallm^ powder  even  less  soluble  than 
caffeine,  and  is  absorbed  with  difficulty  when  given  alone.     It  is  generally 


288  SUBSTANCES  ACTING  AFTER  ABSORPTION 

prescrilicd  in  dosos  of  0.5  G.  (8  grs.)  three  times  a  da}'',  but  larger  quantities 
may  be  given.  Solutions  of  salicylate  of  sodium  dissolve  it  much  more  readily 
than  pure  water. 

Theobromin.^3  et  Sodii  Salicylas  (B.  P.),  Diuretine  is  a  double  salt  of 
sodium-thcobromine  with  the  salicylate  of  sodium  and  is  soluble  in  one  part 
of  water;  it  contains  40  per  cent  of  theobromine  and  35  per  cent,  of  salicylic 
acid.    The  dose  is  10-20  grs.  (0.6-1 .2  G.)  either  in  powder  form  or  in  solution. 

Agurme  differs  from  diuretine  only  in  containing  sodium  acetate  instead  of 
salicylate. 

Theocine,  an  artificial  theophjdline,  is  a  white  crystalline  powder,  slightly 
soluble  in  water.    Dose,  0.2-0.3  G.  (3-5  grs.)  in  powder  or  tablets. 

It  is  preferable  in  therapeutics  to  use  the  pure  principles  rather  than  such 
impure  forms  as  Guarana  (U.  S.  P.),  or  Kola  nut. 

Therapeutic  Uses. — The  action  of  caflFeine  on  the  central  nervons 
system  has  led  to  its  employment  in  a  number  of  different  conditions. 
Thus,  in  nervous  exhaustion  it  may  be  used  to  stimulate  the  l)rain,  and 
in  collapse  its  action  on  the  respiratory  centres  has  been  found  of 
value.  In  narcotic  poisoning  with  failing  respiration,  caffeine  may  be 
used  to  stimulate  the  centre  in  place  of  strychnine  or  atropine;  in 
opium  poisoning  more  particularly,  strong  coffee  has  long  been  used, 
but  caffeine  might  be  substituted  with  advantage.  Its  stimulant 
action  on  the  brain,  and  more  especially  on  the  respiration,  renders 
it  an  antidote  in  dangerous  cases  of  alcoholic  poisoning  also.  Some 
forms  of  migraine  and  headache  are  relieved  by  caffeine,  but  in  others 
it  seems  rather  to  intensify  the  pain;  this  effect  probably  arises  from 
the  action  on  the  brain  and  may  be  compared  to  the  relief  of  fatigue; 
headache  is  often  treated  by  a  mixture  of  caffeine  and  one  of  the  anti- 
pyretic series,  such  as  phenacetine. 

Caffeine  has  been  used  in  diseases  of  the  heart  on  the  sup])osition 
that  it  increases  the  power  of  the  heart  like  digitalis,  for  which  it  is 
often  said  to  be  a  substitute.  But  it  has  not  any  action  on  the  heart 
in  such  quantities  as  can  be  used  in  therapeutics,  and  its  use  for  this 
purpose  is  not  founded  on  any  accurate  clinical  observations.  Its 
reputation  as  a  cardiac  stimulant  may  probably  arise  from  its  efficacy 
in  removing  dropsy  in  heart  disease,  but  this  is  the  result  of  its  renal 
action  and  the  heart  is  not  affected  directly. 

In  their  action  on  the  kidney  the  members  of  the  caffeine  series 
stand  preeminent,  no  other  drug  producing  such  a  copious  flow  of  urine 
as  either  caffeine  or  theobromine.  As  has  been  explained  already,  the 
latter  is  to  be  preferred  to  caffeine  as  a  diuretic,  antl  may  be  u.sed  in 
all  cases  in  which  there  is  a  pathological  accumulation  of  fluid  in  the 
body,  whether  of  cardiac,  hepatic,  or  renal  origin.  The  results  are 
most  l)rilliant,  however,  in  cases  of  cardiac  dropsy,  and  here  it  may 
be  prescribed  along  with  one  of  the  digitalis  series.  It  nnist  be  em- 
phasized, however,  that  in  these  cases  it  cainiot  supplant  tligitalis,  but 
merely  aids  in  the  removal  of  the  fluid.  In  cases  of  hepatic  dropsy, 
cairciiie  and  theobromine  have  also  proxed  of  .service,  although  here 
the  treatment  can  only  be  considered  ])alliative.  In  renal  dropsy 
(hcobroiiiiiic   h;is  l)(>en   used   with   sonicwhal    \arial)le  results;  it   does 


CAFFEINE 


289 


not  seem  to  increase  the  albumin  in  the  urine,  but  not  infrequently 
little  or  no  diuresis  follows  its  administration.  This  is  only  to  be  expected 
where  the  renal  cells  are  in  such  a  condition  as  to  be  incapable  of  stimula- 
tion. Where  the  disease  is  less  developed,  the  members  of  this  series 
produce  the  usual  increase  in  the  secretion.  The  question  of  the  use 
of  these  diuretics  in  renal  disease  is  still  undecided  and  requires  further 
accurate  observation.  In  experimental  nephritis  in  animals  they  often 
act  efficiently  in  washing  out  the  detritus  of  the  tubules,  but  it  is 
unknown  whether  they  have  any  permanent  beneficial  effect. 

Fig.  22 


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Action  of  theobromine  in  cardiac  dropsy.  A  case  of  cardiac  dropsy  treated  with  diure- 
tine  (theobromine-sodium  salicylate)  during  the  period  marked  with  the  black  line  below. 
Dose,  10  grs.  three  times  a  day.  The  urine  per  day  in  ounces  is  marked  in  the  unbroken 
line.  The  body  weight  fell  continuously  (dotted  line)  as  the  dropsy  disappeared,  and 
when  the  normal  weight  of  almost  80  pounds  was  reached,  the  diuresis  became  less  marked, 
as  there  was  no  longer  so  much  fluid  to  draw  upon. 

Inflammatory  eft'usions  do  not  seem  to  be  lessened  to  any  marked 
extent  by  either  cafteine  or  theobromine. 

Other  "efficient  diuretics  are  the  saline  diuretics  (p.  292),  and  the 
mercurial  salts.  Digitalis  and  its  allies  also  promote  diuresis,  but 
mainly  indirectly  by  improving  the  circulation. 


Coffee  and  Tea. 

Coffee  is  not  used  in  medicine,  but  in  view  of  its  immense  dietetic 
importance  it  may  be  mentioned  here  in  what  respects  it  differs  from 
the  pure  cafTeine.  The  coft'ee  bean  contains  about  0.6-0.7  per  cent, 
caffeine,  and  a  cup  of  coffee  is  equivalent  to  1^-3  grs.  of  caffeine  along 
with  some  volatile  substances,  such  as  furfuralcohol,  produced  by 
the  roasting;  these  have  been  called  ('off eon  and  resemble  in  their 
action  the  volatile  oils. 
19 


290  SUBSTANCES  ACTING  AFTER  ABSORPTION 

Tea  contains  a  larger  percentage  of  caffeine  (about  lf-2  {)er  cent.), 
but  as  less  tea  is  used  than  coffee,  each  cup  may  be  considered  to  con- 
tain 1 T-3  grs.  In  green  tea  there  is  a  considerable  quantity  of  a  volatile 
oil  which  also  passes  into  the  infusion,  and  the  flavor  of  black  tea  also 
arises  from  volatile  substances  (Theon).  Both  black  and  green  tea  con- 
tain about  7  per  cent,  of  tannic  acid,  but  this  is  only  extracted  slowly. 
The  bitter  taste  in  tea  that  has  been  prepared  too  long  is  due  to  the 
tannic  acid  passing  into  solution. 

The  wakefulness  and  the  relief  from  fatigue  which  are  produced 
by  tea  and  coffee  are  undoulitedly  due  to  the  caffeine  contained  in 
them,  and  are  to  be  ascribed  to  the  central  action  chiefly,  although 
its  action  on  the  muscles  may  also  be  of  some  value  here.  On  the 
other  hand,  the  feeling  of  well-being  and  comfort  produced  by  coffee 
after  a  full  meal  is  similar  to  the  carminative  effects  of  the  volatile 
oils  and  appears  to  be  due  to  the  local  action  in  the  stomach  of  the 
volatile  con.stituents  of  coffee.  Apart  from  this  local  action,  these 
volatile  bodies  seem  to  have  no  effect  whatever  on  the  economy.  It 
is  stated  that  caffeine  accelerates  slightly  the  action  of  the  digestive 
ferments  outside  the  body,  but  that  coffee  and  tea  retard  it.  And  when 
coffee  and  tea  are  introduced  directly  into  the  stomach  of  animals, 
the  former  is  found  to  cause  a  transient  rise  in  the  secretory  activity, 
while  the  latter  arrests  secretion  at  once;  but  it  is  possible  that  the 
psychical  effect  of  the  taste  in  man  may  alter  this  effect.  Coffee  is  said 
to  increase  the  peristaltic  movements  of  the  intestine,  while  caffeine 
has  no  effect  on  them.  There  is  a  widespread  belief  that  excessive 
tea-drinking  disturbes  gastric  digestion  and  this  has  generally  been 
attributed  to  the  tannic  acid  contained  in  it.  It  is  not  unlikely  that  the 
caffeine  and  theophylline  may  also  play  a  part  in  this  gastric  action 
by  causing  irritation  of  the  mucous  membrane. 

It  was  formerly  stated  that  coffee  lessened  the  tissue  change  and 
that  it  ought  therefore  to  be  included  among  foods,  but  it  has  been 
shown  conclusively  that  far  from  lessening  the  metabolism  of  the  body, 
coffee  and  tea  increase  it,  the  amount  of  urea  and  carbonic  acid  excreted 
being  considerably  augmented  by  their  use.  This  is  only  to  be  expected 
from  the  increased  activity  of  the  nervous  centres,  which  leads  to 
increased  movement  and  increased  consumption. 

Chocolate  contains  theobromine  (0.5-1  per  cent.),  instead  of  caf- 
feine, and  besides  this  a  large  amount  of  fat  (cacao-butter,  15-50  i)er 
cent.),  starch  and  albumins.  The  theobromine  does  not  possess  the 
stimulant  action  of  caffeine  on  the  nervous  system,  and  chocolate  may 
therefore  be  taken  where  coffee  or  tea  produces  wakefulness.  The 
starch  and  fat  are  assimilated  by  the  tissues  so  that  chocolate  is  a  true 
food.  But  Neumann  finds  that  cocoa  retards  the  absorption  of  the 
proteins  and  fats  of  the  food,  especially  those  forms  of  cocoa  in  which 
the  fat  lias  been  partially  removed.  On  the  other  hand,  cocoa  with  a 
large  percentage  of  oil  delays  the  gastric  secretion  and  may  give  rise 
to  a  feeling  of  heaviness  and  discomfort  in  the  stomach.  Its  con- 
tinued use   may   cause  dysi)epsia,  j)artly  from    this  cause   and    i)artly 


CAFFEINE  291 

from  theobromine  acting  on  the  gastric  mucous  meml)rane.  There  is 
no  question  that  the  food  value  of  cocoa  and  chocoUite  is  often  over- 
estimated. It  allays  hunger,  but  this  is  only  in  part  from  its  being 
a  food,  the  local  detrimental  effect  on  the  gastric  mucous  membrane 
tending  to  lessen  appetite. 

Bibliography. 

Schmiedcherg.  Arch.  f.  exp.  Path.,  ii,  p.  62.  Ber.  deutsch.  Chem.  Gesellsch.,  xxxiv, 
p.  2550. 

Archangelsky.     Arch,  internat.  de  Pharmacodyn.,  vii,  p.  405. 

Bock.     Arch.  f.  exp.  Path.,  xliii,  p.  317. 

Filehne.     Arch.  f.  Anat.  iind  Phys..  1886,  p.  72. 

V.  Schroder.     Arch.  f.  exp.  Path.,  xxii,  p.  39;   xxiv,  p.  85. 

Albanese.     Ibid.,  xxxv,  p.  449;  xliii,  p.  305. 

Bondzynski  u.  Gottlieb.     Arch  f.  exp.  Path.,  xxxvi,  p.  45;    xxxvii,  p.  385. 

Heerlein.     Pfliiger's  Arch.,  hi,  p.  165. 

Sobieranski  and  Modrakowski.     Pfliiger's  Arch.,  xcviii,  pp.  135,  217. 

Kraepelin.  Ueber  die  Beeinflussung  einfacher  psychischer  Vorgange  durch  eitiige 
Arzneimittel  (Jena,  1892)  and  Psychqlog.  Arbeiten,  i,  p.  378;    iii,  p.  203. 

Rivers  and  Webber.     Journ.  of  Phys.,  xxxvi,  p.  33. 

CuUis.     Journ.  of  Phys.,  xxxiv,  p.  250. 

Erdmann.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlviii,  p.  233. 

Gourewitsch.     Arch.  f.  exp.  Path.,  Ivii,  p.  214. 

Pawinsky.     Ztschr.  f.  khn.  Med.,  xxiii,  p.  440;    xxiv,  p.  315. 

Neumann.     Arch.  f.  Hygiene,  Iviii,  p.  1. 

V.  Furth.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxvii,  p.  389. 

Kriiger.  Bericht.  d.  deutsch.  chem.  Gesell.,  1899,  pp.  2818,  2677,  3336.  Arch.  f. 
exp.  Path.  u.  Pharm.,  xlv,  p.  259.    Ztschr.  f.  phys.  Chem.,  xxi,  p.  169;   xxxvi,  p.  1. 

Ach.     Arch.  f.  exp.  Path.  u.  Pharm.,  xliv,  p.  319. 

Cushny  and  Van  Naten.     Arch,  internat.  de  Pharmacodynamie,  ix,  p.  169. 

Anten.     Ibid.,  vii,  p.  455. 

Allard.     Deutsch.  Arch.  f.  klin.  Med.,  Ixxx.     (Theocine.) 

hnpens.     Arch,  internat.  de  Pharmacodyn.,  x,  p.  463.     (Methylxanthine.) 

Stenstrom.     Biochem.  Ztschr.,  xlix.  p.  225.     (Glycsemia.) 

Barcroft  and  Straub.     Journ.  of  Phys.,  xli,  p.  145. 

Sollman  and  Pitcher.     Journ.  of  Pharm.  and  Exp.  Ther.,  iii,  pp.  19,  267,  609. 

Boycott  and  Ryffcl.     Journ.  of  Pathology,  xvii,  p.  458. 

Hedinger.     Deutsch.  Arch.  f.  klin.  Med.,  c,  p.  305. 

Minor  Diuretics. 

A  large  number  of  vegetable  drugs  have  enjoyed  a  re])utation  in  the 
past  as  diuretics  but  are  passing  into  disuse.  Many  of  them  owe  their 
position  merely  to  the  large  quantities  of  water  in  which  they  are  taken; 
and  some  of  them,  such  as  barley,  only  lend  body  and  taste  to  water. 
Others  ha\-e  a  slight  diuretic  action  in  themselves  but  are  superfluous 
since  the  introduction  of  caffeine  and  its  allies. 

Uva  Ursi,  the  leaves  of  the  bearberry,  Arctostaphylos  Uva  Ursi,  and  of  alUed 
plants,  contains  two  glucosides,  Arbutin  and  Methylarbutin,  along  with  large 
quantities  of  tannin  and  some  inactive  bodies.  These  glucosides  are  decom- 
posed by  tlie  action  of  acids  or  of  emulsin  into  glucose  and  hydroquinone  or 
methylhydroquinone,  and  tliis  change  seems  to  occur  in  the  body,  for  some 
hydroquinone  appears  in  the  urine  though  most  of  the  arbutin  is  e.xcreted 
unchai^bged;  it  is  not  unlikely  that  the  decomposition  occurs  from  bacterial 
action  in  the  intestine. 


292  SUBSTANCES  ACTING  AFTER  ABSORPTION 

Uva  ursi  is  found  to  have  some  diuretic  action,  which  is  obviouslj^  due  to 
its  acting  on  tlie  renal  epithehuni,  and  the  urine  is  found  to  undergo  putre- 
faction much  more  slowly  than  usual.  Both  the  diuretic  and  the  antiseptic 
action  appear  to  be  due  to  the  undecomposed  arbutin,  though  the  hj'droqui- 
none  may  reinforce  the  glucoside  in  retarding  putrefaction. 

The  urine  is  often  dark  in  color  after  uva  ursi  or  arbutin,  and  this  tint  deep- 
ens when  it  is  allowed  to  stand,  from  the  hydroquinone  undergoing  further 
oxidation;  a  similar  change  occurs  in  carbolic  acid  poisoning.  When  decompo- 
sition of  the  urine  occurs  in  the  bladder,  as  in  cystitis,  the  urine  may  have  this 
dark  color  when  passed. 

Large  quantities  of  uva  ursi  cause  nausea,  vomiting,  and  diarrhcea,  but 
Lewin  states  that  this  disturbance  of  the  alimentary  canal  may  be  avoided 
by  administering  the  glucosides  instead  of  the  cruder  preparations. 

Buchu,  the  leaves  of  several  species  of  Barosma,  contains  a  volatile  oil,  which 
is  excreted  by  the  kidneys  and  increases  the  urine  slightly;  it  also  has  a  feeble 
antiseptic  action  in  the  urine. 

Scoparius,  the  tops  of  the  common  broom  plant  (Cytisus  scoparius),  con- 
tains a  resinous  substance,  scoparin,  which  seems  to  act  on  the  kidney  as  a  mild 
diuretic  and  accounts  for  the  reputation  which  broom-tops  have  long  enjoyed. 
The  alkaloid  sparteine,  which  also  occurs  in  scoparius,  has  no  action  on  the 
kidney. 

Many  other  resinous  bodies  are  used  in  popular  medicine  to  increase  the  urine, 
but  have  little  or  no  effect.  Among  these  may  be  mentioned  Zea,  or  cornsilk, 
and  Chimaphila  or  pipsissewa.  Cubebs,  Copaiba,  and  Cantharides  have  some 
action  as  diuretics  but  are  more  useful  for  their  other  effects. 


Preparations. 

Uva  Ursi  (U.  S.  P.),  Uvse  Ursi  Folia  (B.  P.),  the  leaves  of  Arctostaphylos 
Uva-ursi  (bearberry). 

Fluidexiractum  Uvoe  Ursi  (U.  S.  P.),  2  c.c.  (30  mins.). 

Infusum   Uvce   Ursi  (B.  P.),  ^-1  fl.  oz. 

Arbutin  has  been  advised  in  closes  of  1-4  G.,  in  sweetened  solution. 

Buchu  (U.  S.  P.),  Buchu  Folia  (B.  P.),  the  leaves  of  Barosma  betuUna. 

Flaidextractum  Buchu  (U.  S.  P.),  2  c.c.  (30  mins.). 

Infusum  Buchu  (B.  P.),  1-2  fl.  oz. 

Scoparius  (U.  S.  P.),  Scoparii  Cacumina  (B.  P.),  the  tops  of  Cytisus  scoparius 
or  broom,  is  used  in  the  form  of  an  infusion  (B.  P.  1-2  fl.  oz.),  or  a  decoction 
(1  oz.  to  the  pint  of  water),  |  pint  in  twentj^-four  hours. 

Therapeutic  Uses. — These  drugs  are  all  used  as  mild  diuretics  and  disinfectants 
of  th(^  uriiiaiy  tract,  and  are  generally  prescribed  along  with  more  powerful 
remedies.  They  give  relief  in  catarrh  and  inflannnation  of  the  bladder  by  dilut- 
ing the  urine  and  thus  rendering  it  less  acid  and  less  irritant  to  the  inflamed 
nmcous  membranes. 


VIII.    SALINE  DIURETICS. 

The  amount  of  urine  is  increased  by  all  solids  which  are  eliniinateil 
by  the  kidney,  as  well  as  by  an  excess  of  fluid  in  the  blood.  For  the 
kidney  is  unal)le  to  excrete  solids  except  in  sohition,  and  every  niok'cule 
wliicli  is  passed  through  it  carries  with  it  a  certain  amount  of  water  to 
an;;iiM'nt  the  secretion.  Oidy  substances  whicli  can  circulate  in  tlH>  body 
in  considerabk'  (jnantities  can  l)e  used  to  increase  the  urine  in  this  wa\-, 
and  in  practice  the  chief  diuretics  of  this  class  are  couii)risc(l  in  the 
indill'ercnt  salts  and  similar  harndess  bodies.    In  order  to  act  as  diuretics 


I 


SALINE  DIURETICS  293 

these  must  be  readily  absorbed  from  the  alimentary  tract  and  this 
excludes  a  large  class  of  salts  which  increase  the  urine  greatly  when  they 
are  injected  intravenously,  but  which  are  absorbed  with  difficulty  and 
are  therefore  used  mainly  for  their  effects  on  the  intestine  (see  Saline 
Cathartics,  p.  101). 

Among  the  saline  diuretics  are  the  chlorides  of  sodium,  potassium 
and  ammonium,  though  these  are  seldom  prescribed  for  this  purjjose; 
their  diuretic  action  is  seen,  however,  in  the  treatment  at  spas  and 
watering-places.  The  cerebral  action  of  the  bromides  precludes  their 
use  as  diuretics,  though  an  increased  secretion  of  urine  accompanies 
their  use  in  therapeutics.  The  iodide  of  potassium  is  often  added  to 
other  diuretics  to  reinforce  their  action,  but  is  liable  to  induce  other 
symptoms  when  given  in  large  quantities.  The  typical  saline  diuretics 
are,  however,  the  nitrates  of  the  alkalies  and  the  urea  group. 

The  Nitrates  have  a  cool,  saline  taste,  and  ordinary  doses  taken  in 
water  have  no  effect  except  an  augmented  flow  of  urine.  Very  large 
quantities  taken  in  concentrated  solution  may  cause  gastro-intestinal 
irritation,  giving  rise  to  pain  in  the  stomach  region,  nausea,  vomiting 
and  sometimes  diarrhoea,  and  blood  may  be  present  in  the  vomited 
matter  and  in  the  stools.  The  urine  is  often  abundant,  but  may  be 
scanty  or  entirely  suppressed.  These  symptoms  may  be  followed  by 
great  muscular  weakness,  apathy,  collapse,  and  eventually  coma  and 
death.  At  the  autopsy  the  stomach  and  intestines  are  found  red  and 
congested,  and  very  often  contain  blood  extravasations.  The  kidney 
is  said  to  have  presented  the  symptoms  of  acute  nephritis  and  haemor- 
rhages in  some  cases  of  poisoning. 

When  dilute  solutions  of  the  nitrates  are  used,  much  less  irritation 
is  induced,  and,  in  fact,  large  quantities  may  be  taken  thus  without 
causing  any  symptoms  whatever  except  diuresis. 

Action. — -The  effects  of  nitrates  are  for  the  most  part  those  of  an 
indifferent  and  diffusible  salt,  but  it  is  possible  that  this  may  be  rein- 
forced by  some  further  irritant  action,  for  smaller  quantities  of  the 
nitrates  than  of  the  chlorides  are  sufficient  to  induce  irritation,  and 
solutions  of  the  nitrates  isotonic  with  the  blood  cause  irritation  and 
congestion  in  the  intestine  and  are  slowly  absorbed.  This  irritant 
effect  of  the  nitrates  has  been  explained  by  Binz  and  Barth  as  the 
result  of  the  reduction  of  the  nitrates  to  nitrites  in  the  alimentary 
canal  and  tissues,  but  no  symptoms  of  nitrite  action  seem  to  have  been 
observed  in  cases  of  poisoning  with  nitrates.  Haldane  has  recently 
show-n  that  nitrite  is  formed  from  the  nitrate  used  in  the  preservation 
of  meat  by  salting,  and  that  some  nitrous-oxide  hsemoglobin  is  formed 
and  gives  a  bright  red  color  to  the  meat.  The  presence  of  this  pigment 
may  perhaps  explain  the  red  color  of  the  intestine  in  some  cases  of 
poisoning  in  which  extravasations  of  blood  are  not  marked. 

The  nitrates  have  long  been  used  as  diuretics,  more  especially  the 
nitrate  of  potassium.  The  diuresis  is  generally  attributed  to  the  salt- 
action,  but  there  may  be  in  addition  a  true  stimulation  of  the  kidney 
similar  to  that  observed  under  the  action  of  manv  other  drugs  which 


294  SUBSTANCES  ACTING  AFTER  ABSORPTION 

are  irritant  to  the  bowel.  The  nitrate  of  i)otassiuni  is  generally  con- 
si(ler(>(l  a  ])etter  diuretic  than  tiie  sodium  salt. 

'riic  Fate  of  the  Nitrates  in  the  Body  is  still  ol)scure  owinji;  to  difliculties 
in  their  ((uantitative  estimation.  Some  of  that  ingested  undergoes 
reduction  in  the  alimentary  tract  and  tissues,  for  the  nitrite  reactions 
are  given  by  some  organs  and  by  the  urine.  And  it  seems  likely  that 
a  portion  may  undergo  still  further  reduction  to  ammonia  or  some  of 
its  compounds.  Most  of  it  appears  in  the  urine  as  nitrate  when  large 
doses  are  given,  but  some  investigators  state  that  after  moderate 
quantities  in  man  (1-3  G.)  they  could  observe  no  nitrate  in  the  urine, 
the  whole  having  undergone  some  change  in  the  passage  through  the 
body.  Some  of  the  nitrate  seems  to  be  excreted  in  the  saliva  and 
perspiration,  possibly  unchanged,  although  it  is  rapidly  reduced  to 
nitrite  in  these  secretions,  and  may  in  fact  be  changed  to  this  form 
in  the  secretory  cells. 

Urea  in  the  course  of  its  excretion  through  the  kidney  carries  with  it 
a  considerable  amount  of  water,  and  when  injected  intravenously  is  a 
powerful  diuretic.  It  is  rapidly  absorbed  from  the  intestine  and  is 
practically  devoid  of  action  in  the  tissues  even  in  large  doses. 

Ammonium  Acetate  and  Citrate  are  indifferent  salts  but  undergo 
oxidation  in  the  tissues  and  finally  form  urea  which  acts  as  a  diuretic 
in  passing  through  the  kidney.  They  were  formerly  supposed  to  in- 
crease the  secretion  of  sweat  but  this  action  is  insignificant. 

Preparations. 

Potes.su  Nitras  (U.  S.  P.,  B.  P.),  Nitre,  Saltpetre  (KNO3),  0.5  G.  (7^  grs.), 
B.  P.,  5-20  grs;  colorless  crystals  with  a  cool,  saline  taste,  very  soluble  in  water; 
prescribed  in  dilute  solution. 

Urea  (CO(NH2)2),  colorless  crystals  with  a  cool  saline  taste,  soluble  in  equal 
parts  of  water.    Dose  1-4  G.  (15-60  grs.),  in  solution. 

Therapeutic  Uses. — The  saline  diuretics  are  seldom  used  except  as 
ingredients  of  diuretic  mixtures;  e.  g.,  along  with  digitalis,  or  to  render 
the  urine  more  dilute  and  thus  to  reduce  its  acidity  in  irritation  of  the 
genito-urinary  tract.  They  were  formerly  emi)loye(l  largely  in  fevers 
and  in  various  disorders  of  the  metabolism,  such  as  rheumatism  or 
gout,  but  in  none  of  these  have  they  proved  useful.  The  nitrates  are 
to  be  given  with  care  when  there  is  any  irritation  of  the  stomach  and 
intestine.  Authorities  differ  as  to  whether  these  diuretics  may  be 
prescribed  in  irritation  of  the  kidney,  but  in  every  case  they  ought 
to  be  well  diluted. 

Paper  impregnated  with  saltpetre  is  used  in  asthma  by  burning 
it  in  the  sick  room,  when  the  pyridine  and  nitrites  relieve  the  spasms 
by  relaxing  the  bronchial  muscles.  Saltpetre  may  be  used  in  cigars 
or  cigarettes  for  the  same  purpose,  and  the  tobacco  may  contain  also 
the  leaves  of  belladonna  or  some  of  its  allies,  as  these  have  a  special 
action  on  the  bronchial  muscle. 


PERIPHERAL   NERVOUS  ACTION  295 


BiBLIOCKAl'HY. 

Binz  el  Gcriinger.     Arch,  iritcruat.  de  Pharmacodyn.,  ix,  p.  441. 

Littlejohn.     Edinburgh  Med.  Journ.,  1885,  p.  97. 

Roehmann.     Zts.  f.  Physiol.  Chem.,  v,  p.  233. 

Weyl.     Virchow's  Arch.,  xcvi,  p.  462;    ci,  p.  175;    cv,  p.  187. 

Richet.     Comptes  rend.  d.  1.  Soc.  de  Biol.,  1886,  xxxviii,  p.  480. 

Heffter.     Ergebnisse  der  Physiologie,  ii,  1,  p.  112. 

Haldane.     Journ.  of  Hygiene,  i,  p.  115. 

Rod.     Arch.  f.  [Anat.  u.)  Physiol.,  1901.  p.  534. 


PERIPHERAL  NERVOUS  ACTION. 

A  considerable  number  of  alkaloitls  act  by  interrupting  the  passage 
of  impulses  from  the  central  nervous  system  to  the  peripheral  muscles 
and  organs  in  the  same  way  as  if  the  nerves  were  divided  by  opera- 
tion, while  others  have  the  opposite  effect  of  generating  impulses  in  the 
periphery  which  arouse  these  peripheral  organs  with  results  which  are 
identical  with  those  following  stimulation  of  the  nerves  supplying  these 
organs.  The  point  of  action  of  these  alkaloids  has  been  definitely 
shown  in  all  cases  not  to  be  the  nerve  fibres  themselves  but  the  appa- 
ratus in  which  they  terminate.  No  poison  is  known  that,  circulating  in 
the  blood,  affects  the  nerve  fibres  directly;  all  eft'ects  which  at  first  sight 
appear  to  suggest  this  have  been  proved  to  arise  from  action  at  the 
origin  of  the  neuron  in  the  central  nervous  system  or  at  its  termina- 
tion in  the  periphery.  Among  these  terminations,  the  peripheral  ones 
of  the  afferent  nerves  (Fig.  23,  Ac)  seem  peculiarly  resistant  to  the 
action  of  .drugs,  for  with  the  exception  of  aconitine  and  its  allies,  no 
drug  is  known  to  affect  these  when  it  reaches  them  by  way  of  the  cir- 
culation; on  the  other  hand  many  drugs  exercise  a  powerful  action  on 
them  when  applied  to  them  directly,  that  is,  in  quantities  which  if 
carried  in  the  blood  would  prove  fatal  from  action  elsewhere. 

The  efferent  nerves  are  divided  into  two  great  classes  which  differ 
in  many  respects  (Fig.  23).  The  first  consists  of  those  which,  emerging 
from  the  central  nervous  system  run  direct  to  the  voluntary  muscles 
and  terminate  in  expansions  on  the  muscle  fibres  (Fig.  23,  III).  Certain 
drugs,  of  which  curara  is  the  type,  interrupt  the  connection  between 
these  nerves  and  the  muscles,  so  that  stimulation  of  the  nerve  no  longer 
causes  contraction  of  the  muscle,  although  direct  stimulation  of  the 
muscle  has  its  usual  effect.  Other  alkaloids  {e.  g.,  nicotine,  phy.sostig- 
mine),  which. apparently  act  on  the  same  point  as  curara  but  in  the 
opposite  direction,  cause  fibrillary  twitching  of  the  muscle  fibres;  but 
after  curara,  nicotine  and  physostigmine  are  ineffective  unless  in  very 
large  quantities  and,  on  the  other  hand,  the  effects  of  a  small  amount 
of  curara  may  be  removed  by  those  drugs. 

The  second  group  of  efferent  nerve  fibres  are  known  as  the  autonomic 
system  and  end  in  a  network  around  ganglion  cells.  From  these  ganglion 
cells,  fibres  proceed  which  again  terminate  in  a  network  over  a  number 
of  organs  and  muscles,  which  are  not  generally  under  the  control  of 


296 


SUBSTANCES  ACTING  AFTER  ABSORPTION 


tlie  will  and  are  known  as  the  vegetative  organs.  An  impulse  travelling 
from  the  central  nervous  system  to  such  an  organ  as  the  heart  thus 
passes  through  two  sets  of  terminations,  those  in  the  gangha  and  those 
on  the  muscle  or  gland  cell.  There  are  thus  two  points  at  which  drugs 
may  interrupt  the  passage  of  impulses  or  at  which  they  may  originate 
new  impulses.  The  network  around  ganglion  cells  is  not  known  to  be 
atTcctcd  by  any  alkaloid,  but  the  ganglion  cell  which  is  enclosed  is  the 
seat  of  action  of  a  number  of  poisons,  of  which  the  type  is  nicotine. 
Stimulation  of  the  ganglion  cells,  such  as  occurs  under  small  quantities 


Fjg.  23 


-Ac 


Diagram  of  the  peripheral  nervous  system  and  its  connections  with  the  central  axis. 
/,  an  autonomic  nerve  originating  from  the  cranial  division  (C),  and  terminating  in  a 
ganglion  A',  from  which  a  fibre  runs  to  involuntary  muscle;  //,  an  autonomic  sympathetic 
nerve  rising  in  the  dorso-lumbar  cord  (D-L)  and  passing  to  a  ganglion  from  which  a  fibre 
runs  to  unstriated  muscle;  III,  a  nerve  from  the  cervical  cord  running  to  striated  muscle; 
IV,  a  sensory  nerve  from  the  skin  to  the  cervical  cord;  V,  an  inhibitory,  and  VI,  a  motor 
sympathetic  fibre  running  to  ganglion  cells  from  which  fibres  reach  involuntary  muscle. 
A'^,  ganglia  where  nicotine  acts;  At,  myoneural  junctions  of  cranial  autonomic  nerve, 
where  atropine  acts;  C  indicates  the  point  where  curara  acts;  Ac,  sensory  ends  (aconi- 
tine);  Ad,  sympathetic  myoneural  junctions  (adrenaline);  E,  motor  sympathetic  endings 
(ergotoxine  and  adrenaline). 


of  nicotine,  has  the  same  result  as  electrical  stimulation  of  the  nerve 
fibres  central  to  the  ganglion  (i)reganglionic)  or  between  the  ganglion 
and  the  peripheral  organs  (postganglionic) ;  the  same  effect  follows 
nicotine  after  the  preganglionic  fibres  are  divided,  but  no  action  is  seen 
if  the  postganglionic  fibres  are  dixided  or  if  their  connections  with 
the  organs  are  paralyzed  by  other  drugs.  Paralysis  of  the  ganglion 
cells,  such  as  is  caused  by  large  doses  of  nicotine,  has  the  efTect  of  cutting 
off  the  im|)ulses  from  the  central  nervous  system  and  electric  stinuilation 
of  the  j)rcganglionic  fibres  is  iiiell'ectivc,  while  stimulation  of  the  i)ost- 


PERIPHERAL  NERVOUS  ACTION  297 

o;an,2;li()iHe  fibres  has  its  usual  effect,  and  drugs  acting  on  the  termina- 
tions of  these  fibres  are  unchanged  in  action. ^ 

AH  the  autonomic  gangha  react  in  the  same  way  to  nicotine,  l)ut 
it  is  otherwise  with  the  connections  of  the  postganglionic  neurons  with 
the  organs,  which  are  the  only  other  points  at  which  drugs  can  act  on 
the  path  from  the  central  nervous  system  to  the  periphery.  Here 
it  is  found  that  certain  alkaloids  react  with  some  terminations  and 
not  with  others,  and  in  some  cases  this  has  been  correlated  with  their 
anatomical  origin,  in  others  with  their  physiological  function.  The 
autonomic  system  is  divided  into  two  great  groups,  the  sympathetic, 
which  originates  in  the  thoracic  and  lumbar  spinal  cord,  and  the  cranio- 
sacral which  rises  from  the  cranial  and  sacral  segments ;  the  connections 
of  the  postganglionic  fibres  of  these  in  the  organs  show  marked  diver- 
gences in  their  reaction  to  drugs.  Thus  adrenaline  has  the  same  effect 
as  stimulating  the  whole  of  the  sympathetic  nerves  (except  the  sweat 
nerves)  and  has  no  effect  on  the  craniosacral  system;  and  it  has  been 
shown  to  exercise  its  action  on  the  connections  between  the  postgang- 
lionic fibres  and  the  muscle.  Ergotoxine  similarly  selects  the  sym- 
pathetic system,  but  only  those  of  its  fibres  which  transmit  motor 
impulses,  the  inhibitory  fibres  remaining  unaft'ected;  and,  again,  the 
action  is  on  the  same  neuromuscular  connections  of  the  postganglionic 
fibres.  Stimulation  by  drugs  of  these  neuromuscular  connections  has  the 
same  effect  as  stimulation  of  the  nerve  fibres;  paralysis  cuts  off  the 
impulses  from  the  central  nervous  system,  and  also  from  the  ganglia 
and  postganglionic  fibres.  The  cranial  autonomic  fibres  are  selected 
by  atropine  and  muscarine,  though  their  action  is  not  limited  to  these; 
many  of  the  effects  of  atropine  can  be  shown  to  be  due  to  its  inter- 
rupting the  nerve-muscle  path  of  the  cranial  autonomic  system,  while 
similarly  muscarine  stimulates  the  same  points.  On  the  other  hand, 
some  of  their  effects  appear  to  arise  from  action  at  similar  points  on 
sympathetic  postganglionic  fibres.  Not  infrequently  the  motor  inner- 
vation of  an  organ  is  derived  from  the  craniosacral  division,  while  the 
inhibitory  originates  in  the  sympathetic  or,  vice  versa,  the  cranial  may 
be  inhibitory  and  the  sympathetic  augmentor;  in  these  instances  the 
exact  action  of  a  drug  may  be  difficult  to  determine  owing  to  the  fact 
that  stimulation  of  the  augmentor  has  the  same  effect  as  paralysis  of 
the  inhibitory  terminations. 

It  was  formerly  taught  that  these  drugs  act  on  the  terminations  of  the 
nerves  which  are  recognizable  histologically.  But  it  has  been  shown 
in  many  instances  that  the  action  may  be  elicited  in  an  organ  whose 
nerves  have  been  divided  and  have  degenerated,  and  in  which  no  nerve 
terminations  survive.     It  is  obvious,  therefore,  that  the  drugs  do  not 

1  Anatomically  the  network  round  the  ganglion  cell  corresponds  to  the  nerve  ends 
in  voluntary  muscle  and  the  enclosed  ganglion  cell  to  the  muscle  fibre.  It  is,  therefore, 
interesting  to  find  that  a  number  of  drugs  which  act  on  the  myoneural  junction  in  muscle 
also  affect  the  ganglion  cells;  examples  are  curara  and  its  allies  and  nicotine.  On  the 
other  hand  some  alkaloids  which  act  on  the  myoneural  junctions  in  voluntary  muscle 
affect  the  myoneural  junction  of  the  postganglionic  fibres  (physostigmine). 


298  SUBSTANCES  ACTING  AFTER  ABSORPTION 

produce  tlioir  effects  by  action  on  the  anatomical  nerve  end,  but  on 
something  l\'ing  between  it  and  the  organ.  This  hypothetical  point 
has  been  termed  the  myoneural  junction  and  is  supposed  by  Langley 
to  contain  specific  receptors  which  combine  with  the  poisons.  The 
essential  characteristic  of  the  myoneural  junction  lies  in  the  fact  that 
it  does  not  degenerate  with  the  nerve  and  therefore  is  presumably  of 
muscular  origin,  while  on  the  other  hand  it  is  not  contractile  for  it  may 
be  paralyzed  {e.  g.,  by  curara)  without  the  contractility  of  the  muscle 
being  altered.  It  is  convenient  to  continue  the  use  of  the  words  nerve 
ends  or  terminations  in  describing  the  action  of  these  alkaloids,  but 
these  must  be  understood  to  connote  not  the  anatomical  structures 
but  something  intervening  between  them  and  the  contractile  substance. 


K.   CURARA  GROUP. 

Curara,  woorara,  urari  or  woorali,  is  an  arrow  poison  used  by  the 
natives  of  South  America,  who  prepare  it  by  extracting  the  bark  of 
plants  of  the  genus  Strychnos,  such  as  S.  toxifera. 

Different  preparations  of  curara  were  found  by  Boehm  to  contain  different 
alkaloids.  That  formerly  obtainable  owed  its  activity  to  Curarine,  but  the 
curara  now  exported  contains  Tubocurarine,  which  resembles  curarine  in  its 
action,  and  Curine,  a  weaker  poison,  which  has  an  entirely  different  effect. 
Another  preparation  examined  by  hun  contained  three  alkaloids,  Protocurine, 
Protocuridine  and  Protocurarine,  the  last  of  which  is  the  most  powerful  of 
all  the  curara  alkaloids.  Most  of  the  experiments  on  which  the  statements 
regarding  curara  action  ai-e  based,  were  performed  with  the  crude  drug,  but 
the  alkaloids  seem  to  have  a  very  similar  effect,  with  the  exception  of  curine. 

Action. — The  chief  effect  of  curara  is  the  arrest  of  all  voluntary 
movements  tlirough  an  interruption  of  the  connections  between  the 
peripheral  nerves  and  the  striated  muscle  fibres.  In  the  mammal  the 
muscles  give  way  one  after  the  other  until  the  animal  lies  helpless  on 
the  ground.  It  can  still  move  its  limbs,  but  cannot  recover  its  ordi- 
nary position,  and  soon  the  limbs  become  totally  paralyzed  and  the 
respiratory  movements  alone  persist,  although  they  too  are  slow,  weak 
and  jerky.  Eventually  the  respiration  ceases  also,  and  asphyxia  fol- 
lows but  is  not  betrayed  by  the  usual  convulsions  owing  to  the  motor 
impulses  being  unable  to  reach  the  muscles.  The  heart  soon  fails 
from  the  asphyxia  and  not  through  the  direct  action  of  the  poison. 

In  the  frog  similar  symptoms  are  seen,  but  here  the  arrest  of  the 
respiration  is  not  necessarily  fatal,  as  the  skin  carries  on  the  exchange 
of  gases,  and  recovery  not  infrequently  occurs  after  two  or  even  five 
days  of  complete  paralysis.  The  cause  of  the  curara  paralysis  was 
demonstrated  by  the  classical  researches  of  Claude  Bernard  and  Kolli- 
ker.  If  the  sciatic  nerve  of  the  frog  be  stimulated  during  the  par- 
alysis no  movement  follows,  but  if  the  artery  of  one  leg  be  ligatured 
before  the  application  of  the  poison  this  limb  remains  unparalyzed 
and  reacts  to  reflex  irritation,  while  the  rest  of  the  body  is  perfectly 


CURARA  GROUP  299 

motionless.  Tliese  facts  can  only  be  interpreted  in  one  way;  the 
paralysis  is  peripheral  and  not  central,  and  may,  therefore,  he  due  to 
action  either  on  the  muscle,  the  nerve  trunks,  or  the  intermediate 
structures.  That  it  is  not  due  to  the  nniscle  is  shown  by  the  fact  that 
direct  stimulation  causes  the  same  movement  as  usual.  On  the  other 
hand,  in  the  experiment  in  which  the  artery  is  ligatured,  stimulation 
of  the  nerves  above  the  ligature,  that  is,  where  the  poison  has  access 
to  the  nerve  fibres,  causes  contraction,  so  that  the  nerve  trunks  do  not 
seem  affected.  This  may  be  shown  in  another  way;  if  a  nerve-muscle 
preparation  be  made  and  the  nerve  be  laid  in  a  solution  of  curara,  con- 
traction of  the  muscle  still  occurs  on  stimulation  of  the  nerve,  but  if 
the  muscle  be  laid  in  the  curara  solution  stimulation  of  the  nerve  has 
no  effect,  while  direct  stimulation  still  causes  contraction.  Curara 
therefore  acts  on  the  connection  between  the  nerve  and  muscle  within 
the  muscle  itself  and  paralyzes  it  without  previous  stimulation. 

Action  on  Nerve-ends. — Since  the  investigations  of  Bernard  and 
Kolliker,  the  action  of  curara  has  been  known  to  be  peripheral,  and 
it  has  been  tacitly  accepted  that  it  could  be  localized  in  the  anatomical 
structure  known  as  the  motor  end-plates.  Of  late  years  facts  have 
been  accumulating  which  seemed  difficult  to  reconcile  with  this  view, 
and  Langley  has  recently  shaken  its  foundations  by  showing  that  curara 
continues  to  act  after  the  muscle  plate  has  lost  its  function.  For  the 
action  of  nicotine  on  the  muscles  is  opposed  by  curara,  not  only  in 
normal  muscles,  but  also  in  those  in  which  the  nerves  and  nerve-endings 
have  degenerated  through  section.  The  action  of  curara  here  must  be 
exerted,  not  on  the  end-plate,  but  on  some  undegenerated  substance, 
which  has  been  termed  the  myoneural  junction  and  which  normally 
serves  to  transfer  the  nerve  impulse  from  the  nerve-plate  to  the  actual 
contractile  substance  of  the  muscle. 

Here,  perhaps,  better  than  elsewhere  it  can  be  shown  that  the  condition 
of  "paralysis"  produced  by  poisons  is  analogous  to  that  termed  by  physiol- 
ogists "fatigue."  It  is  known  that  on  stimulating  a  nerve  rapidly  by  electric 
shocks,  or  otherwise,  the  muscle  at  first  contracts  with  every  stimulation,  but 
eventually  ceases  to  respond,  owing  to  "fatigue"  of  the  nerve  ends,  that  is, 
to  their  inability  to  transmit  impulses  from  the  nerve  to  the  muscle.  If  now 
the  response  to  nerve  stimulation  of  a  muscle  to  which  a  minute  quantity  of 
curarine  has  been  applied,  be  compared  with  that  of  a  normal  one,  it  is  found 
that  the  poisoned  one  ceases  to  respond  much  sooner  than  the  other — i.  e., 
its  nerve  ends  become  fatigued  much  sooner.  The  more  curara  is  applied, 
the  sooner  does  it  fatigue,  until  at  last  no  response  at  all  can  be  elicited  from 
it.  The  "paralysis"  of  the  nerve  terminations  by  curara  then  is  of  the  same 
nature  as  physiological  "fatigue,"  and  other  conditions  of  "paralysis"  are 
also  analogous  to  those  produced  by  over-stimulation,  though  the  exact  condition 
of  the  paralyzed  organ  may  not  be  the  same  as  the  fatigued  one.  Thus  there 
is  some  reason  to  suppose  that  in  the  curarized  terminations  the  substance 
which  is  normally  consumed  in  transmission  is  present,  but  in  a  form  which 
cannot  be  utilized,  while  in  fatigue  it  has  all  been  exhausted  by  the  impulses 
which  have  already  passed  through. 

Curara  acts  first  on  the  nerves  of  the  toes,  ear  and  eye,  later  those 
supplying  the  limbs,  head  and  neck,  and,  last  of  all,  those  supplying 


300  SUBSTANCES  ACTING  AFTER  ABSORPTION 

the  muscles  of  respiration.  At  first  slight  inoveinents  can  be  per- 
formed, because  single  impulses  can  pass  through  the  nerve  ends, 
but  sustained  contractions  such  as  are  necessary  to  preserve  the  equi- 
librium, caimot  be  maintained,  and  the  animal  therefore  falls.  The 
intermittent  impulses  to  the  respiratory  nuiscles  still  allow  time  in  the 
interval  for  the  recovery  of  the  terminations,  but  as  the  intoxication 
proceeds  the  number  of  impulses  which  can  pass  through  becomes 
fewer  and  fewer,  and  the  movement  therefore  assumes  more  and  more 
the  character  of  a  jerk  and  eventually  ceases. 

Small  doses  do  not  afi'ect  the  innervation  of  unstrijjcd  muscle,  and 
the  strict  demarcation  of  its  action  is  seen  very  distinctly  in  organs 
which  consist  partly  of  striated  and  partly  of  imstriated  fibres.  Thus 
in  the  oesophagus,  the  striated  muscle  fibres  no  longer  contract  on 
stimulation  of  the  vagus  after  curara,  while  the  unstriated  continue  to 
respond  as  usual.  In  the  iris  of  the  mammals,  which  consists  of  un- 
striated muscle,  curara  has  no  effect,  while  the  striated  muscle  of  the 
bird's  iris  ceases  to  respond  to  stimulation  of  the  motor  oculi,  but 
contracts  on  direct  stimulation.  The  terminations  of  the  nerves  in  the 
heart  are  not  affected,  but  the  nerves  of  the  lymph  hearts  of  the  frog 
are  paralyzed.  The  nerve  ends  in  striated  muscle  in  invertebrates 
appear  to  be  immune  to  curara  (Straub).  The  nerve  fibres  seem  un- 
affected by  curara,  for  stimulation  causes  the  usual  electrical  changes 
in  them. 

The  Sympathetic  Ganglia  are  paralyzed  by  large  doses,  and  stimulation 
of  the  preganglionic  nerve  fibre  has  no  eft'ect.  For  example  stimulation 
of  the  vagus  does  not  slow  the  heart,  and  stimulation  of  the  chorda 
tympani  does  not  cause  secretion  because  the  impulses  fail  to  pass 
the  ganglia  on  their  course.  The  terminations  of  the  postganglionic 
fibres  are  not  affected  apparently,  for  stimulation  has  its  usual 
effect. 

The  peripheral  terminations  of  the  afferent  or  sensory  ner\es  seem 
unaffected,  for  if  the  artery  of  one  leg  be  ligatured  before  the  application 
of  curara,  reflex  movements  may  be  obtained  in  it  from  stimulation  of 
any  part  of  the  body,  while  if  the  sensory  terminations  were  paralyzed, 
reflexes  could  be  elicited  only  by  the  irritation  of  parts  to  which  the 
poison  had  not  penetrated,  i.  e.,  from  the  ligatured  leg. 

The  central  nervous  system  is  said  to  be  stimulated  by  large  quantities 
of  curara.  The  heart  is  not  directly  aft'ected,  but  large  quantities  may 
paralyze  the  vagus  ganglia  and  release  the  heart  from  inhibition.  At 
the  same  time  the  blood-pressure  may  fall  from  paralysis  of  the  ganglia 
on  the  vasoconstrictor  nerves.  The  movements  of  the  intestine,  spleen 
and  other  organs  are  sometimes  accelerated  through  a  siniihir  paralysis 
of  the  ganglia  on  inhibitory  nerves. 

Metabolism. — The  cessation  of  the  ordinary  movements  after  curara 
and  under  artificial  respiration  has  generally  been  accompanied  by  a 
marked  decrease  in  the  oxygen  abs()ri)tion  and  the  carbonic-acid  excre- 
tion, but  Frank  and  (iebhard  state  that  this  is  not  the  case  when  the 
temperature   is   maintained   by   the   ai)plication   of   heat.     Sugar  and 


CURARA  GROUP  301 

lactic  acid  are  often  found  in  the  urine  after  curara,  but  this  is  (hie  to 
partial  asphyxia  and  not  to  the  direct  action  of  the  poison;  the  olvco- 
gen  of  the  liver  and  muscles  disappears  from  the  same  cause. 

Curara  is  excreted  by  the  kidneys  apparently  unchanged.  It  has 
long  been  known  that  this  arrow  poison  may  be  swallowed  with  impu- 
nity, pro^'ided  there  is  no  wounded  surface  in  the  mouth  or  throat,  and 
that  it  is  therefore  perfectly  safe  to  suck  the  poison  from  a  wound. 
This  has  been  explained  in  various  ways,  some  holding  that  the 
absorption  from  the  stomach  is  so  slow  that  the  kidneys  are  able  to 
excrete  the  poison  as  fast  as  it  reaches  the  blood  and  that  this  prevents 
its  accumulating  in  sufficient  quantity  to  affect  the  tissues.  Others 
suppose  that  the  liver  retains  and  destroys  it,  and  a  third  view  is  that 
it  is  rendered  innocuous  in  passing  through  the  stomach  walls. 

The  characteristic  action  of  curara  on  the  myoneural  junction  in 
striated  muscle  is  antagonized  to  some  extent  by  physostigmine, 
nicotine,  and  some  other  alkaloids. 

Curiae,  the  second  alkaloid  found  by  Boehm  in  some  specimens  of  curara, 
is  a  much  less  poisonous  body  than  curarine.  It  possesses  some  action  on 
the  heart,  the  same  appearances  following  its  injection  in  the  frog  as  after 
digitalin  and  veratrine,  while  in  mammals  the  rhythm  is  slow  even  after 
paralysis  of  the  inhibitory  mechanism. 

Curara  is  an  extract  of  varying  constitution  and  strength  and  the  active  con- 
stituents are  freely  soluble  in  acidulated  water,  Attempts  have  been  made  to 
use  curara  in  various  forms  of  convulsive  spasms,  but  without  adequate  results. 

Paralysis  of  the  terminations  of  the  motor  nerves  in  striated  muscle— the 
so-called  "  Curara-Action"— is  elicited  by  a  large  number  of  poisons,  but  m 
few  of  them  is  it  the  first  effect  of  their  application.  Many  drugs  mduce  it 
only  when  injected  in  large  quantities  and  at  the  end  of  a  scries  of  phenomena 
produced  by  their  action  on  other  parts  of  the  body;  it  is  observed  much  more 
frequently  in  frogs  than  in  mammals,  and  is  often  of  little  importance  com- 
pared to  "the  other  symptoms.  Among  the  bodies  which  resemble  curara  more 
closely  in  their  action,  the  peripheral  paralysis  playing  the  chief  role  in  their 
effects,  are  the  ammonium  compounds  formed  from  the  natural  alkaloids  by 
the  substitution  of  an  alkyl,  e.  g.,  methylstrychnine,  amylquinine,  etc.i  Some 
of  the  ammonium  salts  and  many  of  the  alkyl  combinations  of  ammonium, 
phosphorus,  arsenic  and  of  several  metals,  also  cause  it. 


Bibliography. 

C.  Bernard.     Comptes  rendus,  xxxi,  p.  533;   xliii,  p.  825. 

Kolliker.     Virchow's  Archiv,  x,  p.  3. 

Overend  and  Tillie.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxvi,  p.  1;   xxvii,  p.  1. 

Boehm.     Ibid.,  xxxv,  p.  16;  Iviii,  p.  265;  Ixiii,  p.  177. 

Santesson.     Ibid.,  xxxv,  p.  23.    Skand.  Arch.  f.  Physiol.,  x  and  xi. 

Fiihner.     Arch.  f.  exp.  Path.  u.  Pharm.,  Iviii,  p.  1. 

Langley.     Journ.  of  Physiol.,  xxxvi,  p.  347;    xxxvii,  pp.  165,  285. 

Edmunds  and  Roth.     Amer.  Journ.  Physiol.,  xxiii,  p.  28. 

Straub.     Pfliiger's  Arch.,  Ixxix,  p.  379. 

Meyer.     Ergebnisse  der  Physiol.,  i  (2),  p.  200. 

Frank  and  Gebbard.     Ztschr.  f.  Biol.,  xliii,  p.  117. 

'  Boehm  has  recently  stated   that  tubocurarine,   which  is  the  active  constituent  of 
much  of  the  modern  curara,  is  really  one  of  those  methyl  bases  (methylcurine). 


302  SUBSTANCES  ACTING  AFTER  ABSORPTION 


C  online. 

Coniine  is  one  of  the  simpler  derivatives  of  Piperidine,  which  is  obtained 
from  Pyridine  by  reduction.  A  series  of  alkaloids  may  be  formed  from  piperi- 
dine by  substituting  methyl,  ethyl,  propyl  or  other  alkyls  for  hydrogen,  and 
one  of'  these,  propyl-piperidine,  is  the  natural  alkaloid  coniine  and  was  the 
first  alkaloid  to  be  formed  synthetically. 

Pyridine.  Piperidine.  Coniine. 

"CH  CH2  CH2 

HC/\CH  H2C/\CH=  H2C/\CH2 

HC\/CH  H2C\/CH2  H2C\/CH— C3H7 

N  NH  NH 

Coniine  is  found  in  Hemlock  (Conium  maculatum),  along  \nth  two  nearly 
allied  alkaloids,  Methjlconiine  and  Conhydrine.  The  action  of  these  and  of 
the  other  simple  piperidine  compounds  resembles  that  of  coniine,  but  is  much 
weaker. 

Symptoms.— The  general  symptoms  induced  in  man  by  poisonous  doses  of 
coniine  are  weakness,  languor  and  drowsiness  which  does  not  pass  into  actual 
sleep.  The  movements  are  weak  and  unsteady,  the  gait  is  staggering,  and 
nausea  and  vomiting  generally  set  in,  along  with  profuse  salivation.  In  most 
cases  the  intelligence  remains  clear  to  the  end,  as  is  related  of  the  death  of 
Socrates  from  hemlock  poisoning,  but  in  some  instances  imperfect  \'ision  and 
hearing  have  been  noted.  The  pupils  are  somewhat  dilated.  Tremors  and 
fibrillary  contractions  of  the  muscles  are  often  seen  in  animals,  and  some 
observers  state  that  actual  convulsions  occur.  The  breathing  becomes  weaker 
and  slower  and  death  occurs  from  its  arrest. 

Action.— Coniine  does  not  possess  any  action  of  importance  on  the  central 
nervous  system.  It  is  possible  that  in  fatal  poisoning  the  respiratory  centre 
may  be  depressed,  but  most  observers  believe  that  the  terminal  asphyxia  is  due 
to  paralysis  of  the  nerve  terminations  in  the  respiratory  muscles.  And  the  twitch- 
ing and  tremor  which  are  sometimes  seen,  appear  to  arise  from  a  partial  paralysis 
of  the  peripheral  nerves  similar  to  that  seen  under  curara.  It  also  resembles 
curara  in  paralyzing  the  sympathetic  ganglia,  but  this  paralysis  seems  to  be 
preceded  by  a  short  stage  of  stimulation;  the  ganglia  are  affected  by  quantities 
of  coniine  which  are  insufficient  to  cause  paralysis  of  the  nerves  to  voluntary 
muscle,  but  its  action  on  these  ganglia  is  not  so  powerful  as  that  of  nicotine, 
and  the  details  of  this  action  may  therefore  be  left  for  discussion  under  the 
latter  drug. 

The  heart  is  affected  through  the  stimulation  and  subsequent  paralysis  of 
the  ganglia  on  the  inhibitory  fibres,  which  leads  first  to  slowing  and  later  to 
some  acceleration  of  the  pulse.  The  blood-pressure  is  increased  for  a  siiort  time 
from  stimulation  of  the  ganglia  on  the  course  of  the  vasoconstrictor  nerves. 
The  respiration  is  sometimes  accelerated  slightly  at  first  but  soon  becomes 
slow  and  labored,  and  then  irregular,  and  finally  ceases  while  the  heart  is  still 
strong.  The  red  blood  cells  of  the  frog  show  numerous  vacuoles  in  coniine 
poisoning  and  these  persist  long  after  recovery  (Giirber). 

Coniine  is  rajiidlv  excreted  in  the  urine,  so  that  its  action  passes  off  very  soon 
even  when  quite  large  doses  are  taken.  The  treatment  of  coniine  poisoning 
therefore  cou.sists  in  evacuation  of  the  stomach  and  artificial  respirat.ion. 

Piperidine  acts  in  the  same  way  as  coniine,  but  more  weakl>-,  while  methyl- 
and  (■tliyl-i)ii)eri(liiie  stand  between  them  in  toxicity. 

Pyridine  resembles  piperiflim;  in  most  features  but  does  not.  paralyze  the 
ganglia  nor  increase  the  blood-pressure.  It  is  excreted  in  the  urine  as  methyl- 
pyridiiie,  a  combination  between  it  and  the  alkyl  occurring  in  the  tissues.  A 
similar  synthesis  occurs  between  methyl  and  tellurium  (see  Tellurium). 


CUR  AH  A  GROUP  303 

Quinoline  and  isoquinolinc  cause  in  mammals  a  condition  of  collai)se  similar 
to  that  seen  under  the  antipyretics  and  the  benzol  compounds. 

Hemlock  or  Conium,  long  widely  used  in  therapeutics,  has  failed  to  maintain 
its  position  on  more  accurate  investigation  and  has  passed  into  disuse. 

Bibliography. 

Prevost.     Arch,  de  Physiol.  (2),  vii,  p.  40. 

Boehm.     Arch.  f.  exp.  Path.  u.  Pharm.,  xv,  p.  432. 

Hayashi  and  Muto.     Ibid.,  xlviii,  p.  356. 

Gilrber.     Arch.  f.  Anat.  und  Phys.,  1890,  p.  401. 

Cushny.     Journ.  of  Exp.  Med.,  i,  p.  202. 

Moore  and  Row.     Journ.  of  Phys.,  xxii,  p.  273. 

Stockman.     Journ.  of  Phys.,  xv,  p.  245. 

Cohn.     Zts.  f.  phys.  Chem.,  xviii,  p.  112;   xx,  p.  210. 

Gelsemium. 

Gelsemium  sempervirens  (Yellow  Jasmine  or  Carolina  .lasmine)  contains 
several  alkaloids,  of  which  Gelsemine^  is  inactive  in  mammals,  while  a  mixture 
of  two  or  more  alkaloids,  which  is  known  as  Gelseminine,  is  a  poison  of  the 
coniine  type  and  is  the  real  active  principle  of  the  drug  as  far  as  mammals  are 
concerned. 

Action. — The  symptoms  of  gelsemium  poisoning  resemble  .those  of  coniine 
so  closely  that  the  reader  may  be  referred  to  the  description  given  under  the 
latter.  There  is  here  again  a  question  whether  the  final  asphyxia  is  due  to 
paralysis  of  the  respiratory  centre  or  of  the  nerve  terminations,  but  most  in- 
vestigators lean  to  the  view  that  the  action  is  central  and  arises  from  a  gradual 
depression  of  the  medullary  centre. 

The  pupil  is  very  widely  dilated  by  gelseminine  when  a  solution  is  applied 
locally  to  the  eye,  much  less  so  in  general  poisoning,  in  which  the  respiration 
generally  fails  before  the  pupil  is  fully  dilated.  The  power  of  accommodation 
is  also  entirely  lost  when  gelseminine  or  gelsemium  tincture  is  applied  to  the 
eye.  This  mydriatic  effect  has  not  been  explained,  but  the  most  plausible 
suggestion  would  seem  to  be  that  gelseminine  paralyzes  the  terminations  of  the 
oculomotor  nerve  in  the  eye  in  the  same  way  as  atropine.  Gelseminine  differs 
from  atropine  in  its  behavior  to  other  nerves,  however,  for  it  paralyzes  the 
inhibitory  cardiac  fibres  and  the  chorda  tympani  through  acting  on  the  gan- 
glionic structures  on  their  course  and  not  on  the  extreme  terminations.  Its 
action  on  the  ganglia,  as  far  as  it  is  known,  resembles  that  of  coniine,  but  it 
does  not  cause  any  increase  in  the  arterial  tension,  such  as  is  observed  under 
this  poison. 

The  tincture  of  gelsemium  (U.  S.  P.,  B.  P.),  has  been  emploj^ed  in  doses  of 
5-15  mins.  in  facial  neuralgia,  and  a  mixture  of  the  alkaloids  has  been  applied 
locally  to  dilate  the  pupil,  but  has  never  attained  any  wide  use. 

Bibliography. 

Ringer  and  Murrell.     Lancet,  1876,  i,  p.  82. 

Putzeys  and  Romiee.  Memoire  sur  Taction  physiologique  de  la  Gelsemine,  Bruxelles, 
1878. 

Cushny.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxi,  p.  49. 

Sparteine. 

Another  alkaloid  which  resembles  coniine  closely  in  its  action  is  Sparteine, 
which  is  found  in  the  common  broom  plant  (Spartium  or  Cytisus  scoparius), 
and  in  various  species  of  lupines.  It  is  a  pyridine  derivative  possessing  the 
formula  C15H26N2,  and  is  a  fluid,  but  forms  crystalline  salts. 

'  Gelsemine  is  frequently  known  as  gelseminine,  a  use  of  the  term  which  leads  to 
some  confusion,  and  which  is  not  based  on  the  history  of  the  drug. 


304  SUBSTANCES  ACTING  AFTER  ABSORPTION 

Action. — The  gcMicral  effects  of  sparteine  are  aUiiost  identical  with  those  of 
coniine,  but  it  seems  very  probable  that  the  central  nervous  sj^stem  is  little 
affected  by  it,  the  whole  of  the  phenomena  pointing  to  a  paralysis  of  the  motor 
nerve  terminations  and  of  the  symjiathetic  ganglia.  Sparteine  has  more  effect 
than  coniine  on  the  heart,  which  it  depresses,  so  that  the  rhythm  is  slow  and  the 
contractions  weak.  When  injected  into  a  vein,  sparteine  induces  less  increase 
in  the  arterial  tension  than  coniine,  probably  because  the  contraction  of  the 
vessels  is  counterbalanced  by  the  weakness  of  the  heart.  No  increase  in  the 
arterial  tension  is  observed  from  the  administration  of  sparteine  internally 
and  even  the  slight  rise  of  pressure  induced  bj^  intravenous  injection  is  of  only 
short  duration. 

Sparteine  is  very  much  less  poisonous  than  either  coniine  or  gelseminine; 
it  proves  fatal  to  animals  by  paralyzing  the  terminations  of  the  phrenic  nerves 
in  the  diaphragm. 

The  slow  pulse  and  slight  rise  of  pressure  observed  in  experiments  in  animals 
when  sparteine  is  injected  intravenously  have  led  some  wTiters  to  ascribe  to 
it  an  action  similar  to  that  of  digitalis,  and  at  one  time  sparteine  was  used  to 
some  extent  as  a  substitute  for  the  latter;  both  experimental  and  clinical 
observations,  however,  go  to  show  that  these  claims  are  quite  unfounded,  and 
sparteine  is  comparatively  little  used  at  the  present  time,  and  possesses  no 
properties  which  are  likely  to  reinstate  it  in  favor. 

Sparteine  sulphate  (U.  S.  P.),  has  been  advised  in  heart  disease  in  doses 
varying  from  J^  gr.  up  to  12  grs.,  but  is  of  no  value.  Its  reputation  appears 
to  have  arisen  from  the  use  of  broom  tops  as  a  diuretic,  but  this  action 
is  not  due  to  the  sparteine,  but  to  scoparin  (p.  292). 

Bibliography. 

Pick.     Arch.  f.  exp.  Path.  u.  Pharm.,  i,  p.  397. 
Masius.     Bull,  de  I'Acad.  Roy.  de  Med.  de  Belgique,  1887. 
Cushny  and  Matthews.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxv,  p.  129. 
Muto  and  Ishizaka.     Ibid.,  1,  p.  1. 

X.  NICOTINE  GROUP. 

Nicotine,  the  well-known  alkaloid  of  tobacco  (Nicotiana  tabacum), 

is  a  volatile  fluid,  possessing  a  strong  alkaline  reaction,  and  forming 

salts  with  acids,  most  of  which  are  amorphous.      It  is  a  combination 

of  pyridine  with  a  hydrated  pyrrol  ring  as  shown  by  the  structural 

formula — 

CH  H2C CH2 


HCr  >C— CHl^        ^CH2 


HC\^        yCn  N— CH3 


N 


Nicotine  is  the  only  constituent  of  tobacco  which  possesses  any 
toxicological  interest,  although  several  other  alkaloids  arc  present  in 
comparatively  small  amounts.  It  is  accompanied  by  a  volatile  oil  in 
dried  tol)acco,  but  this  is  only  developed  during  tlie  processes  of  prepa- 
ration and  seems  to  have  no  action  a])art  from  that  of  the  otlier  volatile 
oils.  Tlie  oilor  and  flavor,  and  probably  the  "strength,"  of  tobacco 
depend  in  part  upon  tiic  (luantity  and  tpudity  of  this  oil,  in  ])art 
on  some  prodiu-ts  of  the  decomposition  of  nicotine.     Absolutely  pure 


I 


NICOTINE  GROUP  305 

nicotine  has  conii)arativeK'  little  odor,  })ut  it  decomposes  when  kept, 
becomes  dark  colored,  and  acqnires  the  characteristic  odor  of  tobacco. 

Nicotine  is  also  found  in  the  pituri  plant  (Duboisia  Hopwoodii), 
the  leaves  of  which  are  used  by  the  Australian  natives  in  the  same  way 
as  tobacco  by  the  civilized  races. 

Lobdine  (CisHasNOs),  an  alkaloid  obtained  from  Lobelia  inflata  or 
Indian  Tobacco,  and  Cytisine,  (CuHuNaO),  the  alkaloid  of  hd)urnum 
(Cytisus  laburnum),  gorse  and  other  plants,  resemble  nicotine  very 
closely  in  action,  and  another  body  of  the  same  type  of  action  is  the 
artificial  quaternary  ammonium  base,  Methijlhordenine. 

These  alkaloids  act  chiefly  on  the  central  nervous  system,  the  sym- 
pathetic ganglia,  and  the  myoneural  junctions  in  voluntary  muscle. 

Symptoms. — Poisonous  doses  administered  to  man  or  other  mammals 
cause  a  hot,  burning  sensation  in  the  mouth,  which  spreads  down  the 
oesophagus  to  the  stomach,  and  is  followed  by  salivation,  nausea,  vomit- 
ing, and  sometimes  purging.  The  breathing  is  quick,  deep  and  labored, 
and  is  often  accompanied  by  moist  rales.  The  pulse  is  generally  slow 
and  sometimes  weak  at  first,  and  then  becomes  very  rapid,  .but  after 
very  large  doses  may  be  first  accelerated  and  then  slow  and  feeble.  Some 
mental  confusion,  great  muscular  weakness,  giddiness  and  restlessness 
are  followed  by  loss  of  coordinating  power  and  partial  or  complete 
unconsciousness.  Clonic  convulsions  set  in  later,  accompanied  by 
fibrillary  twitching  of  various  muscles,  and  eventually  a  tetanic  spasm 
closes  the  scene  by  arresting  the  respiration.  In  other  instances  the 
convulsions  are  followed  by  collapse  with  complete  relaxation  of  the 
muscles,  the  reflexes  disappear,  the  respiration  becomes  slow  and 
weak  and  finally  ceases,  the  heart  continuing  to  beat  for  some  time 
afterward.  Very  large  doses  of  nicotine  may  prove  fatal  within  a  few 
seconds;  the  symptoms  are  those  of  sudden  paralysis  of  the  central 
nervous  system,  including  the  respiratory  centre,  and  no  convulsions 
are  developed. 

In  the  frog  the  same  excitement  and  violent  convulsions  are  seen 
as  in  mammals,  but  the  respiration  soon  ceases,  and  there  follows  a 
''cataleptic"  stage  in  which  the  animal  assumes  a  characteristic  attitude. 
The  fore  legs  are  crossed  in  front  of  the  sternum  and  are  rigid,  the 
thighs  are  at  right  angles  to  the  axis  of  the  body  and  the  legs  are  flexed 
on  them  but  are  not  rigid.  When  a  leg  is  drawn  down  it  at  once  returns 
to  its  original  position,  and  the  frog  still  attempts  to  escape  when  it 
is  aroused.  Fibrillary  contractions  are  observed  in  many  of  the  muscles. 
Somewhat  later,  the  reflexes  disappear,  the  muscles  become  flaccid, 
and  eventually  complete  paralysis  occurs  from  a  peripheral,  curara-like 
action. 

Nicotine  has  but  little  toxic  action  on  the  lowest  invertebrates,  but 
as  the  nervous  system  begins  to  be  dift'erentiated  it  causes  paralysis, 
and  still  higher  in  the  scale  the  paralytic  action  is  preceded  by  a  stage 
of  stimulation. 

Circulation. — The  action  on  the  circulation  is  extremely   complex, 
as  a  number  of  factors  are  involved.     After  moderate  quantities  the 
20 


306 


SUBSTANCES  ACTlSd  AFTER  ABSORPTION 


heart  is  slow  and  nia\-  stand  still  in  diastole  for  a  few  seconds,  but 
then  recovers  gratkially  and  regains  its  former  rhythm  or  becomes 
somewhat  quicker.  The  slow  pulse  is  due  to  stimulation  of  the  ganglia 
on  the  vagus  nerve  (Fig.  24,  N),  exactly  the  same  efiects  being  pro- 


Fig.  24 


Diagram  of  the  regulating  nerves  of  the  heart.  P,  inhibitory  cranial  autonomic 
fibres  (vaRus),  terminating  around  ganglion  cells  in  the  auricle  (..4).  The  axis  cylinders 
issuing  from  these  cells  terminate  on  the  muscular  fibres  of  the  auricle  and  ventricle  (10. 
R,  accelerator  sympathetic  fibres  terminating  around  ganglion  cells  in  the  stellate  gang- 
lion G.  The  axis  fibres  of  these  ganglion  cells  run  through  the  Annulus  Vieussenii  and 
terminate  on  the  muscular  fibres  of  the  auricle  and  ventricle.  A^  N'  points  at  which 
nicotine,  coniine,  curarine,  etc.,  act — the  ganglion  cells  surrounded  by  the  terminations 
of  the  nerves.  M,  points  at  which  muscarine  and  atropine  act — the  terminations  of  the 
fibres  which  arise  from  the  intra-cardiac  ganglia  on  the  cranial  autonomic  path.  E,  points 
at  which  adrenaline  acts — the  myoneural  junction  on  the  sympathetic  path. 

duced  as  by  stimulation  of  the  vagus  fibres  in  the  neck.       It  is  not 
affected  by  section  of  the  cervical  pneumogastric,  as  the  path  from  the 
ganglia  to  the  cardiac  muscle  fibres  is  still  intact,  but  on  the  other      j- 
hand,  it  is  prev^ented  by  atropine,  which  paralyzes  the  terminations 
of  the  postganglionic  fibres,  and  therefore  blocks  the  passages  of  im-       I 


NICOTINE  GROUP  307 

pulses  from  the  ganglia  to  the  muscle.  It  is  also  prevented  by  a  number 
of  drugs,  such  as  curara  and  coniine,  which  paralyze  the  ganglia. 

This  stimulation  of  the  ganglia  is  of  short  duration,  soon  passing 
into  paralysis,  so  that  on  stimulating  the  vagus  after  nicotine  there  is 
no  slowing  of  the  heart  but  often  some  acceleration,  due  to  the  fact 
that  the  accelerating  fibres  running  along  with  the  inhibitory  in  the 
vagus  nerve  have  no  ganglionic  apparatus  in  the  heart,  and  are  therefore 
unaffected  by  nicotine.  Although  inhibitory  impulses  can  no  longer 
reach  the  heart  from  above,  stimulation  of  the  venous  sinus  in  the 
frog  still  causes  arrest  of  the  heart,  since  the  stimulating  current  here 
reaches  the  inhibitory  nerves  beyond  the  paralyzed  ganglia  (Fig.  24,  A'^), 
and  these  preserve  their  usual  irritability.  In  the  same  way  muscarine, 
which  acts  upon  the  postganglionic  inhibitory  terminations  in  the  heart 
muscle  (Fig.  24,  M),  can  slow  the  rhythm  even  after  the  ganglia  have 
been  paralyzed  by  nicotine. 

In  addition  to  its  action  on  the  peripheral  inhibitory  ganglia,  nico- 
tine seems  to  stimulate  the  vagus  centre  in  the  medulla,  as  the  slowing 
is  greater  when  the  vagi  are  intact  than  when  they  are  divided.  But 
apart  from  this  action  on  the  inhibitory  apparatus,  nicotine  also  stimu- 
lates, and  in  large  quantities  paralyzes,  the  ganglia  on  the  accelerator 
fibres,  so  that  when  the  inhibitory  mechanism  has  been  put  out  of 
action  by  atropine,  moderate  quantities  of  nicotine  increase  the  rate, 
while  larger  amounts  paralyze  the  accelerator  ganglia  (N',  Fig.  24)  and 
thus  tend  to  slow  the  heart.  A  further  action  is  said  to  be  exercised  on 
the  heart  muscle  itself,  which  is  first  stimulated  and  then  depressed 
(Wertheimer) . 

On  the  injection  of  nicotine  into  a  vein  or  subcutaneously,  an  im- 
mense augmentation  of  the  arterial  tension  occurs;  this  may  be  due  in 
part  to  stimulation  of  the  vaso-constrictor  centre  in  the  medulla,  but 
is  to  be  ascribed  chiefly  to  stimulation  of  the  ganglia  on  the  course 
of  the  vasoconstrictor  nerves. 

The  constriction  of  the  vessels  can  be  observed  in  many  parts  of  the  body 
■ — mesenter}',  foot,  rabbit's  ear,  etc.  In  these  pai'ts  the  pallor  produced  by 
the  narrowing  of  the  vessels  is  followed  by  redness  and  congestion  owing  to 
the  paralysis  of  the  ganglia,  and  at  the  same  time  the  pressure  falls  to  a  level 
somewhat  below  the  normal.  In  some  parts  of  the  body  no  constriction  of 
the  vessels  occurs;  for  example,  the  dog's  lip  and  mouth  are  congested  first 
and  then  become  pale.  This  flushing  seems  partly  due  to  the  stimulation  of  the 
ganglionic  apparatus  on  the  vaso-dilator  fibres  for  the  lips  and  mouth,  and 
partly  to  the  constriction  of  the  vessels  in  the  splanchnic  area  diverting  the 
blood  current  to  those  parts  which  are  less  abundantly'  supplied  with  con- 
strictor fibres,  for  it  occurs  after  removal  of  the  superior  cervical  ganglion  con- 
taining the  vasodilator  fibres. 

After  a  few  minutes  the  blood-pressure  falls  to  the  normal  level  or 
lower,  but  a  second  injection  again  produces  a  similar  rise  in  the  arterial 
tension,  unless  the  first  was  large  enough  to  weaken  the  ganglia. 

In  the  rabbit  nicotine  tends  to  induce  lesions  of  the  aorta  with  sub- 
sequent calcareous  degeneration,   which  resembles  the  atheromatous 


308  SUBSTANCES  ACTING  AFTER  ABSORPTION 

patclies  seen  in  man.  This  is  due  to  the  \'ery  high  blood-pressure,  and 
similar  effects  are  seen  from  adrenaline  and  from  other  measures  which 
increase  the  blood-pressure,  such  as  pressure  on  the  abdominal  aorta. 

Respiration. — The  respiration  is  at  first  rapid  and  shallow  with  some 
deficiency  in  the  expiratory  movements,  but  after  a  time,  while  main- 
taining the  acceleration,  it  becomes  deeper.  It  is  liable  to  be  inter- 
rupted at  this  stage  by  the  convulsions,  but  if  these  do  not  prove  fatal, 
it  gradually  becomes  slower  while  remaining  deep.  Later,  pauses  in 
the  position  of  expiration  appear,  and  the  movements  become  weaker 
until  they  disappear,  the  animal  dying  of  asphyxia.  The  respiratory 
centre  is  first  stimulated  and  then  depressed  and  paral^^zed  and  its 
failure  is  the  cause  of  death,  the  heart  continuing  to  beat  for  some  time 
afterward  although  slowly  and  weakly. 

The  bronchial  muscle  relaxes  after  a  transient  constriction  when 
nicotine  or  lobeline  is  ingested,  these  changes  being  brought  about  by 
stimulation  of  the  ganglia  on  the  course  of  the  vagus  fibres  which  cause 
contraction  of  the  bronchial  muscle,  and  later  of  those  on  the  sym- 
pathetic fibres  which  inhibit  the  contraction. 

Most  of  the  Secretions  are  increased  temporarily  by  nicotine.  The 
gJands  investigated  have  generally  been  the  salivary,  where  it  is  found 
that  the  secretion  is  increased  by  the  injection  of  small  quantities,  but 
is  afterward  depressed,  while  large  doses  diminish  it  at  once.  The  seat 
of  action  is  again  the  ganglionic  apparatus  on  the  secretory  nerves. 
If  the  chorda  tympani  be  stimulated  in  the  normal  animal  a  large 
secretion  of  saliva  at  once  follows,  but  if  a  sufficient  quantity  of  nicotine 
be  injected,  no  such  effect  follows  its  stimulation.  If,  however,  the 
nerve  fibres  be  stimulated  between  the  ganglion  cells  and  the  gland 
(at  X  in  Fig.  25),  the  secretion  again  follows  as  before.  On  the  other 
hand,  nicotine  increases  the  secretion  whether  the  chorda  be  intact 
or  not,  but  ceases  to  act  if  the  connection  between  the  ganglion  cells 
and  the  gland  be  interrupted.  Nicotine  thus  first  stimulates  and  then 
paralyzes  the  ganglia  on  the  course  of  the  chorda  tympani  and  of  the 
sympathetic  fibres  supplying  the  gland.  Pilocarpine  and  muscarine 
cause  profuse  salivation  after  nicotine  because  tliey  stimulate  the 
postganglionic  terminations  in  the  gland  cells,  and  it  is  therefore  im- 
material whether  the  connection  with  the  central  nervous  system  be 
interrupted  or  not.  On  the  other  hand,  the  reflex  secretion  of  saliva 
normally  produced  by  irritation  of  the  mouth  or  by  chewing  is  prevented 
by  nicotine.  Atropine  stops  the  secretion  produced  by  nicotine  by 
paralyzing  the  postganglionic  terminations. 

The  other  secretory  glands  are  affected  in  the  same  way  by  nicotine, 
their  secretions  l)eing  first  increased  by  the  stiuuilation  of  the  ganglia 
on  the  course  of  their  secretory  nerves,  and  then  being  lessened  by  their 
paralysis.  'J'hus  the  secretion  of  sweat  and  bronchial  mucus  is  found 
to  be  markedly  increased.  The  urine  and  bile  have  not  been  shown 
to  l)e  affected  by  nicotine,  as  their  secretion  does  not  seem  to  be  so 
dependent  ujx)!!  nervous  influences.  The  activity  of  the  suprarenal 
glands  is  increased  l)y  nicotine,  probably  by  its  action  on  the  ganglia 


NICOTINE  GROUP 


309 


on  the  course  of  the  innervatino;  fibres;  this  results  in  an  auj^mented 
secretion  of  adrenahne  into  the  bloodvessels,  which  in  turn  affects  a 
number  of  or<;ans,  such  as  the  iris  and  uterus,  and  introduces  a  new 
complication  in  the  action  of  nicotine. 


Fig.  25 


Diagram  of  the  innervation  of  the  submaxillary  gland.  P,  cranial  autonomic  fibres 
(chorda  tympani),  terminating  around  a  ganglion  cell  in  the  hilus  of  the  submaxillary 
gland.  The  axis  from  this  ganghon  cell  runs  to  the  secretory  epithelium.  R,  sympathetic 
fibres,  terminating  around  a  ganghon  cell  in  the  superior  cervical  ganglion  G.  The  axis 
from  this  cell  runs  to  the  secretory  epithelium.  In  the  diagram  the  nerves  are  represented 
as  running  to  separate  acini.  A'',  N',  ganglion  cells  surrounded  by  the  terminations  of 
the  nerves — the  points  at  which  nicotine  acts.  M,  the  terminations  of  the  secretory  fibres 
connected  with  the  chorda  tympani — the  points  at  which  atropine,  muscarine,  and  pilo- 
carpine act.  E,  the  terminations  of  the  secretory  fibres  connected  with  the  sympathetic 
— the  point  at  which  adrenaline  acts. 

Nicotine  produces  extreme  Nausea  and  Vomiting  when  taken  even 
in  comparatively  small  quantities,  a  fact  which  is  generally  recognized 
by  tyros  in  smoking.  This  may  be  in  part  central  in  origin,  but  is 
mainly  due  to  the  powerful  contractions  of  the  stomach  walls.  This 
contraction  extends  throughout  the  intestinal  tract,  so  that  repeated 
Evacuation  of  the  Bowel  occurs.     Somewhat  larger  quantities  may  lead 


310  SUBSTANCES  ACTING  AFTER  ABSORPTION 


to  a  tetanic  contraction  of  the  whole  intestine  with  ahnost  complete 
obliteration  of  the  Inmen.  This  exaggeration  of  the  peristaltic  con- 
traction is  probably  fine  to  stinuilation  of  the  motor  ganglia  in  the 
intestinal  wall,  and  a  snbseqnent  paralysis  of  these  structnres  leads  to 
a  failnre  of  local  stimuli  to  induce  peristalsis.  A  further  effect  of  nicotine 
in  the  bowel  is  due  to  its  stimulating  the  ganglia  on  the  fibres  of  the 
splanchnic  which  inhibit  the  rhythmical  pendulum  movements.  These 
are  arrested  by  the  injection  of  nicotine,  but  return  in  exaggerated 
form  as  the  ganglionic  stimulation  passes  into  paralysis.  The  mesenteric 
vessels  are  narrowed  at  first  from  stimulation  of  the  ganglia  on  the 
course  of  the  vaso-constrictor  nerves,  but  congestion  follows  the  depres- 
sion of  these  ganglia  and  the  blood-pressure  falls. 

Similar  changes  are  produced  by  nicotine  in  the  bladder,  which  is 
thrown  into  tetanic  contraction.  The  urine  is  therefore  expelled  very 
soon  after  the  injection  of  nicotine  and  this  probably  gave  rise  to  the 
erroneous  view  that  the  renal  secretion  was  increased.  The  uterus  is 
strongly  contracted  in  pregnant  animals,  but  is  inhibited  in  the  non- 
pregnant cat,  in  which  the  inhibitory  nerves  are  more  powerful  than 
the  contractor  ones. 

The  action  of  nicotine  on  the  Pupil  varies  in  different  animals,  for 
while  in  the  cat  and  dog  its  application  either  intravenously  or  locally 
produces  marked  but  transitory  dilation,  in  the  rabbit  partial  con- 
striction sets  in  immediately.  In  cases  of  acute  poisoning  in  man 
contraction  is  generally  seen  at  first  and  is  followed  by  dilatation.  In 
birds  nicotine  causes  very  marked  contraction  of  the  pupil,  appar- 
ently owing  to  direct  action  on  the  muscle  of  the  iris.  The  size  of 
the  {)upil  is  regulated  by  two  sets  of  nerves,  the  motor  oculi  and  the 
sympathetic,  and  the  ciliary  fibres  of  both  of  these  are  interrupted  by 
ganglia  in  their  passage  from  the  brain  to  the  iris,  those  of  the  motor 
oculi  by  the  ciliary  ganglion,  those  of  the  sympathetic  by  the  superior 
cervical  ganglion  (see  Fig.  26,  p.  320);  the  varying  eflFects  of  nicotine 
may  be  due  to  its  stimulating  the  one  ganglion  more  strongly  in  one 
species  of  animals,  the  other  in  another.  It  is  found,  however,  that 
atropine  does  not  remove  the  effects  of  nicotine  on  the  rabbit's  eye, 
which  would  seem  to  indicate  an  action  on  the  muscular  fibres  of  the 
iris.  Several  other  effects  on  the  orbital  muscles  are  seen;  thus  in 
cats  and  dogs  the  nictitating  membrane  is  withdrawn,  the  eye  opens  : 
and  is  directed  forward,  while  in  the  rabbit  these  symptoms  are  pre-  j 
ceded  by  a  stage  in  which  the  nictitating  membrane  is  spread  over  the  * 
cornea  and  the  eye  is  tightly  closed;  these  all  arise  from  stinuilation  and 
subsequent  paralysis  of  the  superior  cervical  ganglion.  ; 

Nicotine,  then,  first  stimulates  and  later  i)aralyzes  all  the  Autonomic 
Ganglia,  whether  applied  locally  to  them  or  injected  into  the  circulation.         ;, 
In  these  ganglia,  the  characteristic  formation  is  the  basket-like  arrange-         i 
ment  of  the  terminations  of  the  entering  nerve,  which  surround  a  large         j, 
nerve  cell  from  which  an  axis  cylinder  runs  to  the  muscle  or  secretory 
cell.    A  nerve  impulse  from  the  central  nervous  system  passes  from  the 
basket  to  the  cell  and  thence  to  the  periphery.    Langley  has  shown  that 


NICOTINE  GROUP  311 

nicotine  acts  on  the  cell  of  the  peripheral  neuron,  and  not  on  the  net- 
work around  it,  for  the  same  effect  is  obtained  from  the  application 
of  the  poison  after  the  network  has  degenerated. 

In  tlie  frog  nicotine  produces  fibrillary  twitching  and  slow,  i)ro- 
longed  contraction  of  the  Muscles,  which  are  not  prevented  by  previous 
division  of  the  nerves  leading  to  them,  but  disappear  on  the  injection 
of  curara;  on  the  other  hand,  the  paralysis  induced  by  curara  may  be 
partially  removed  by  small  quantities  of  nicotine.  This  indicates  that 
the  fibrillary  contractions  arise  neither  from  action  on  the  central  ner- 
vous system  nor  on  the  contractile  substance  of  the  muscle  itself.  And 
Langley  has  recently  shown  that  the  fibrillary  twitching  and  slower 
contractions  occur  in  muscles  in  which  the  nerve  ends  have  degen- 
erated from  division  of  the  nerves,  so  that  nicotine  acts  on  some  recep- 
tive substance  peripheral  to  the  anatomical  nerve  ends  and  intervening 
between  these  and  the  contractile  substance  of  muscle.  A  similar 
effect  is  seen  in  reptiles  and  birds;  in  mammals  the  twitching  of  the 
muscles  is  prevented  by  section  of  the  nerves,  and  is,  therefore,  due  to 
central  action,  but  large  quantities  of  nicotine  cause  paralysis  exactly 
like  curara. 

The  convulsions  seen  in  both  cold-  and  warm-blooded  animals  evi- 
dence the  influence  of  nicotine  on  the  Central  Nervous  System.  The 
spinal  cord  is  thrown  into  a  condition  of  exaggerated  irritability,  and 
the  reflexes  are  correspondingly  increased,  but  the  convulsions  do  not 
seem  to  be  due  so  much  to  the  spinal  cord  as  to  the  medulla  oblongata 
and  hind  brain,  for  they  are  not  tonic  but  clonic  in  character,  and  are 
much  weaker  after  division  of  the  cord  immediately  below  the  medulla 
than  in  the  intact  animal.  The  medullary  stimulation  also  betrays 
itself  in  the  rapid  and  deep  respiration,  and  is  perhaps  in  part  respon- 
sible for  the  inliibitory  slowing  of  the  heart  and  the  rise  in  the  blood- 
pressure.  The  higher  centres  in  the  brain  seem  to  participate  but 
little  in  the  stimulant  action  of  nicotine,  which  is  short-lived,  and 
soon  gives  way  to  marked  depression  of  the  whole  central  nervous 
system,  manifested  in  the  slow^  respiration,  the  low  blood-pressure,  the 
disappearance  of  the  reflex  movements  and  the  final  unconsciousness. 

The  Excretion  of  nicotine  is  probably  carried  on  mainly  by  the  kid- 
neys, for  it  is  found  in  the  urine  very  soon  after  it  enters  the  blood. 
It  has  also  been  detected  in  the  saliva  and  perspiration.  It  has  been 
shown  repeatedly  that  nicotine  and  some  other  alkaloids  are  weakened 
in  toxic  effect  or  rendered  entirely  inactive  by  being  mixed  with  an 
extract  of  the  liver  or  of  the  suprarenal  capsules;  but  no  satisfactory 
explanation  is  forthcoming,  though  there  is  every  reason  to  suppose 
that  much  of  the  nicotine  absorbed  from  the  stomach  and  intestine  is 
thus  modified  in  its  passage  through  the  liver. 

When  small  quantities  of  nicotine  are  ingested  repeatedly,  the  body 
soon  gains  a  certain  Tolerance,  and  no  symptoms  whate\'er  are  pro- 
duced by  doses  which  in  ordinary  cases  would  produce  grave  poison- 
ing. A  familiar  example  of  this  tolerance  is  seen  in  the  practice  of 
smoking.       The  first  use  of  tobacco  in  the  great  majority    of  indi- 


312  SUBSTANCES  ACTING  AFTER  ABSORPTION 

viduals  is  followed  by  vomitiiifj  and  depression,  which  may  even  amount 
to  collapse,  but  after  a  few  experiences  no  symptoms  follow  smoking, 
owing  to  the  cells  of  the  body  becoming  tolerant  of  the  poison  and  learn- 
ing to  destroy  it  more  rapidly  (Dixon  and  Lee).  In  some  individuals 
no  such  tolerance  is  developed,  and  in  every  case  the  tolerance  is 
much  more  limited  and  more  difficult  to  acquire  than  that  for  morphine. 
In  animal  experiments  it  is  often  found  that  while  one  application  of 
nicotine  produces  considerable  ganglionic  stimulation,  the  second  has 
much  less  effect.  This  is  probably  due,  not  to  the  establishment  of 
tolerance,  but  to  the  first  dose  having  produced  primary  stinuilation 
and  then  depression  of  the  ganglia,  this  depression,  while  not  amounting 
to  complete  j)aralysis,  being  sufficient  to  counteract  to  some  exent  the 
stimulant  action  of  the  second  injection.  True  tolerance  is  attained 
very  imperfectly  by  animals  from  the  use  of  repeated  small  doses,  but 
when  larger  amounts  are  used  some  tolerance  is  soon  acquired  (Edmimds) . 
Animals  which  have  acquired  tolerance  for  nicotine  also  resist  the  action 
of  lobeline. 

Therapeutic  Uses. — Lobelia  wds  formerly  used  as  an  emetic,  but  is  unreliable, 
and  is  liable  to  give  rise  to  the  most  alarming  symptoms  of  poisoning.  It  is 
occasionallj^  used  in  the  form  of  the  tincture  (Dose,  U.  S.  P.,  1  c.c,  B.  P., 
5-15  niins.),  to  relax  the  spasm  of  the  bronchial  muscle  in  asthma,  and  may 
also  aid  in  this  condition  by  rendering  the  mucous  secretion  more  fluid  through 
its  nauseating  action.  But  its  effects  must  be  carefully  watched,  as  the  prepara- 
tions seem  to  vary  in  strength,  and  alarming  symptoms  and  even  fatal  results 
have  sometimes  followed  its  use.  In  any  case  it  is  inferior  to  atropine  and  its 
allies  in  this  condition.  Nicotine  and  the  other  members  of  the  group  are 
not  used  in  therapeutics. 

Tobacco. 

Tobacco  had  been  in  use  among  the  aboriginal  tribes  of  America 
before  they  became  known  to  civilization.  It  was  introduced  into 
Europe  soon  after  the  discovery  of  America,  and  its  use  as  an  article 
of  luxury,  beginning  in  England,  soon  spread  to  the  continent,  and  in 
spite  of  papal  bulls  and  numerous  efforts  on  the  part  of  the  secular 
authorities,  has  continued  to  enthral  a  considerable  portion  of  the 
human  race.  The  most  widespread  use  of  tobacco — smoking — is  also 
the  most  ancient  one,  having  been  that  of  the  aboriginal  Indians. 
Snufl'-taking,  introduced  by  P>ancis  II.  of  France,  remained  fashion- 
able for  a  long  time,  but  is  now  almost  obsolete.  Tobacco-chewing 
is  a  more  modern  development,  but  shows  no  signs  of  abatement. 
Curiously  enough,  the  leaves  of  the  pituri  plant,  which  contain  nicotine, 
are  formed  into  a  mass  and  chewed  by  the  natives  of  Australia.  In 
smoking,  snuffing  or  chewing,  nicotine  is  absorbed;  tobacco  smoke 
always  contains  nicotine,  though  the  amount  varies  with  diiferent 
kinds  of  tobacco  and  also  with  the  way  in  which  it  is  smoked;  but  a 
large  proportion  of  that  contained  in  tobacco  passes  over  in  the  smoke 
along  with  pyridine  and  some  of  its  derivatives.  In  snuff  the  nicotine 
is  generally  small  in  amount,  while  in  chewing  tobacco  there  is  generally 
a  \'aryiiig  amount  of  foreign  matter,  such  as  molasses. 


NICOTINE  CROUP  313 

The  enjoyment  derived  from  the  use  of  tobacco  has  never  been 
adequately  explained,  and  it  is  not  even  proved  that  nicotine  is  essential 
to  the  pleasurable  results;  consideration  of  the  pharmacological  effects 
of  nicotine  gives  no  clue,  for  these  are  of  the  opposite  nature.  It  has 
been  suggested  that  smoking  gives  repose  and  thereby  improves  intel- 
lectual work,  but  this  is  denied  by  many  habitual  smokers.  It  has 
also  been  stated,  and  denied,  that  the  mental  energy  is  reduced  by  the 
use  of  tobacco,  and  an  attempt  has  been  made  to  demonstrate  this  by 
measuring  the  amount  of  work  done  with  and  without  tobacco;  but 
investigators  are  not  agreed  on  the  results,  which  probably  depend 
largely  upon  the  individual.  One  fact  is  certain,  that  the  tobacco 
habit  cannot  be  compared  with  the  use  of  such  drugs  as  morphine, 
cocaine,  or  alcohol,  for  it  is  not  taken  with  the  purpose  of  producing 
stimulation  or  depression  of  the  central  nervous  system,  and  it  seems 
doubtful  whether  the  nicotine  ordinarily  absorbed  really  has  any  action 
whatsoever.  Perhaps  the  local  effects  on  the  mouth,  nose  and  throat 
play  a  larger  part  in  the  effects  of  tobacco  than  is  generally  recognized. 
A  certain  amount  of  rhythmic  movement  demanding  no  exertion  seems 
in  itself  to  have  a  soothing,  pleasure-giving  effect,  for  it  is  otherwise 
impossible  to  explain  the  satisfaction  enjoyed  by  many  in  chewing 
tasteless  objects,  such  as  gum  or  straws.  A  curious  fact  which  tends 
to  show  that  tobacco  smoking  is  not  carried  on  for  the  sake  of  the 
nicotine  absorbed,  is  that  the  pleasure  derived  from  a  pipe  or  cigar  is 
abolished  for  many  persons  if  the  smoke  it  not  seen,  as  when  it  is  smoked 
in  the  dark;  and  very  few  blind  men  enjoy  smoking. 

Most  people  may  indulge  in  the  moderate  use  of  tobacco  for  many 
years  with  perfect  impunity,  but  its  excessive  use  is  followed  in  many 
individuals  by  a  number  of  symptoms,  some  of  them  trivial,  others 
indicating  grave  changes  in  important  organs. 

One  of  the  commonest  effects  of  overindulgence  in  tobacco  is  a 
chronic  inflammation  of  the  throat  and  upper  parts  of  the  respiratory 
passages,  leading  to  hoarseness  and  excessive  secretion  of  the  mucous 
glands.  This  is  explained  by  the  constant  application  to  the  throat 
of  an  irritant,  alkaline  vapor,  and  is  probably  not  due  to  the  specific 
action  of  nicotine.  A  similar  irritated  condition  of  the  tongue  is 
frequently  met  with,  more  especially  when  the  hot  vapor  is  constantly 
directed  on  one  part,  as  in  pipe  smoking,  and  it  is  sometimes  stated 
that  the  constant  irritation  thus  produced  renders  the  tongue  and  lip 
more  liable  to  cancerous  disease.  Dyspepsia,  want  of  appetite,  and 
consequent  loss  of  flesh  may  also  be  explained  by  the  local  irritation 
produced  by  the  nicotine  swallowed  in  the  saliva.  A  common  result 
of  the  abuse  of  tobacco  is  palpitation  and  irregularity  of  the  heart, 
which  has  been  attributed  to  changes  in  the  inhibitory  mechanism. 
Another  important  symptom  is  dimness  of  vision,  especially  for  colors, 
and  imperfect  accommodation,  which  may  go  on  to  complete  blindness 
in  one  or  both  eyes.  In  early  cases  the  retina  often  appears  pale,  and 
if  the  condition  persists,  atrophy  of  the  optic  nerve  may  result,  prob- 
ably following  on  degenerative  changes  in  the  ganglion  cells  of  the 


314  -  SUBSTANCES  ACTING  AFTER  ABSORPTION 

macular  region  of  the  retina.  This  tobacco  amblyopia  is  held  by  some 
to  occur  only  when  the  tobacco  habit  is  accompanied  by  alcoholic  excess. 
Smokino;  causes  a  slight  rise  of  bloo(l-j)ressure  in  some  individuals, 
and  this  has  aroused  a])i)rehcnsions  that  it  may  tend  to  favor  arterio- 
sclerosis, but  the  change  is  so  slight  that  these  fears  are  quite  ground- 
less. Nervous  symptoms,  such  as  tremor,  exaggeration  of  the  reflexes, 
headache  and  giddiness,  are  sometimes  developed  in  workmen  in 
tobacco  factories,  but  they  do  not  seem  to  be  induced  by  smoking  or 
chewing  tobacco,  though  depression,  muscular  weakness  and  giddiness 
are  sometimes  com})lained  of.  In  the  great  majority  of  cases  of  chronic 
tobacco  poisoning,  the  symptoms  disappear  on  abandoning  the  habit, 
or  even  on  restricting  the  daily  consumption.  A  series  of  subjective 
and  even  objective  symptoms  are  said  to  be  induced  in  neurotic  subjects 
by  the  sudden  withdrawal  of  tobacco. 

Esser  has  recently  stated  that  chronic  nicotine  poisoning  in  animals 
induces  marked  disturbance  of  the  heart,  and  that  degeneration  of  the 
vagus  fibres  is  recognizable  histologically;  changes  have  also  been 
found  in  the  nerve  cells  of  the  spinal  cord  and  sympathetic  ganglia 
similar  to  those  described  under  chronic  alcoholic  poisoning. 


Bibliography. 

Langley  and  Dickinson  (Journ.  of  Phys.,  xi,  p.  265)  give  all  the  more  important  experi- 
mental literature  up  to  1890. 

Langley,  Langley  and  Sherrington,  Langley  and  Anderson.  Journ.  of  Phys.,  xii,  xiii, 
XV,  and  xxvii,  p.  224;    xxxvi,  p.  347;    xxxvii,  pp.  165,  285. 

Werlheimer  ei  Colas.     Archiv.  de  Physiol.  (5),  iii,  1891,  p.  341. 

Bayliss  and  Starling.     Journ.  of  Phys.,  xxiv,  p.  99. 

Hatcher.     Amer.  Journ.  of  Phys.,  xi,  p.  17. 

Dixon  and  Brodie.     Journ.  of  Phys.,  xxix,  p.  168. 

Esser.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlix,  p.  190. 

Greenwood.     Journ.  of  Phys.,  xi,  p.  573.     (Action  on  Invertebrates.) 

Moore  and  Row.     Journ.  of  Phys.,  xxii,  p.  273. 

Winterberg.     Arch.  f.  exp.  Path.  u.  Pharm.,  xHii,  p.  400. 

Habermann.     Ztschr.  f.  physiol.  Cliem.,  xxxiii,  p.  55. 

Edmunds.     Journ.  of  Pharmacology,  i,  p.  27. 

Dixon  and  Lee.     Quart.  Journ.  Exp.  Physiol.,  v,  p.  373. 

Birch-Hirschfeld.     Arch.  f.  Ophthalmologic,  liii,  p.  79. 

C.  W.  Edmonds.     Amer.  Journ.  of  Phys.,  xi,  p.  79.     (Loheline.) 

Dale  and  Laidlaw.     Journ.  of  Pliarm.  and  Exp.  Thcrap.,  iii,  p.  205.     (Cytisino.) 


XI.     THE  ATROPINE  SERIES. 

The  atropine  series  contains  a  number  of  very  closely  allied  alkaloids 
of  which  the  chief  are  Atropine,  IIi/(>sc!/at)iinp  and  Ilyoscine  or  Scoix)- 
laviine.  They  are  found  in  several  ])lants  of  the  Solanacea^  order,  and 
in  most  cases  several  of  them  occur  together. 

Atropine  may  be  broken  up  by  the  action  of  alkalies  into  an  alkaloid, 
Troivtic,  and  Tropic  Acid.  The  former  is  a  pyridine  comj)()und  very 
closely  allied  to  Eajonine  (see  Cocaine)  as  may  be  seen  by  its  structural 
fornniln,  wliilc  the  latter  is  an  aromatic  acid. 


» 


THE  ATROPINE  SERIES  315 

Atropine. 


Tropine  radicle.  Tropic  acid  radicle. 

CH2— CH CH2 

I  I 

N  (CH3)CH0— CO— CH— Cells 

I  1  I 

CH2— CH CH2  CH2OH 


Atropine  is  racemic  hyoscyamine,  that  is,  it  consists  of  equal  parts  of 
Isevohyoscyamine  and  dextrohyoscyamine,  but,  as  the  latter  is  only 
feebly  active  in  the  body,  the  action  of  atropine  is  practically  that 
of  its  Isevohyoscyamine  half.  La^vohyoscyamine  is  formed  in  the 
plants,  and  is  readily  changed  to  atropine  in  the  plant  cells  and  also 
in  the  process  of  extraction,  so  that  the  relative  proportion  of  the 
isomers  in  the  plants  and  in  the  preparations  varies. 

Hyoscine,  or  Scopolamine,  was  formerly  supposed  to  be  another 
isomer  of  atropine,  but  has  lately  been  shown  to  differ  slightly  in  its 
formula,  which  is  C17H21NO4.  It  is  very  closely  allied  to  atropine, 
and  is  decomposed  into  tropic  acid  and  ScopoJine  {Oscine),  which  is 
nearly  related  to  tropine. 

A  number  of  other  alkaloids  have  been  described  in  different  plants,  genera,lly 
associated  with  one  or  more  of  those  already  mentioned.  But  on  examination 
these  have  generally  j^roved  to  be  mixtures  of  atropine,  hyoscyamine  and 
hyoscine.  Thus  the  Duboisine  of  Duboisia  myoporoides,  the  Mandragorine 
of  IVbxndragora  (Mandrake)  and  the  Daturine  of  Datura  stramonium  have 
all  failed  to  maintain  their  position  as  new  bases  and  have  proved  to  be  mixures 
of  the  established  alkaloids  in  varying  proportions.  Atropamine,  Belladonnwe 
or  Apoatropine  is  found  along  with  atropine  in  some  plants  (belladonna),  and 
may  be  formed  artificially  from  atropine  by  the  removal  of  a  molecule  of  water; 
it  is  a  compound  of  tropine  and  atropic  acid.  Pseudo-kyoscij amine  is  said  to 
differ  from  atropine  and  hyoscyamine  in  some  of  its  chemical  relations,  but 
has  not  been  the  subject  of  much  work  as  yet.  Atroscine  is  isomeric  with  scopo- 
lamine, and  the  same  relation  exists  between  them  as  between  atropine  and 
hyoscyamine. 

After  atropine  had  been  found  to  be  a  compound  of  tropine  and 
tropic  acid,  a  number  of  other  acids  were  attached  to  tropine  in  the 
same  way  as  tropic  acid.  These  artificial  alkaloids  are  known  as  Tro- 
peines,  and  in  action  resemble  atropine  in  some  points  w  bile  differing 
from  it  in  others.  The  only  artificial  tropeine  which  has  as  yet  been 
used  in  medicine  is  the  compound  of  tropine  and  oxytoluic  acid  known 
as  Ilomatropitie.  Scopoleines  have  been  formed  by  substituting  other 
acids  for  the  tropic  acid  of  scopolamine,  but  none  of  them  have  proved 
of  value  in  therapeutics  as  yet. 

It  must  be  understood  that  the  combination  of  tropine  and  its  allies 
with  tropic  acid  does  not  partake  in  any  way  of  the  nature  of  the 
combination  of  an  ordinary  alkaloid,  such  as  morphine,  with  an  acid. 
The  bond  is  the  much  closer  one  seen  in  the  compound  ethers,  and  the 
resulting  substance  is  alkaline  and  combines  with  acids  to  form  salts 
exactlv  as  other  alkaloids  do. 


310  SUBSTANCES  ACTING  AFTER  ABSORPTION 

The  chief  phmts  containing  these  alkaloids  are  Atropa  Belladonna 
(Deadly  nightshade),  Hyoscyamus  niger  (Henbane),  and  Datura  Stra- 
nioninni  (Thornapple). 

Of  less  iinportaiu'C  are  Duboisia  inyoporoides,  Scopola  atropoides,  and  Man- 
dragora  autuinnalis,  or  Atropa  mandragora  (Mandrake);  another  species  of 
Duboisia  contains  nicotine. 

A  number  of  other  Solanacese — e.  g.,  tobacco  and  potato  leaves,  are  said 
to  contahi  small  quantities  of  the  atropine  alkaloids  but  the  quantity  present 
here  is  too  small  to  be  of  any  importance. 

These  alkaloids  all  resemble  each  other  closely  in  the  effects  pro- 
duced by  them  in  animals.  Some  differences  in  the  symptoms  exist, 
however,  and  the  action  of  atropine  alone  will  first  be  described  and 
later  the  points  in  which  that  of  hyoscyamine  and  of  hyoscine  differ 
from  it. 

Atropine  acts  as  a  stimulant  to  the  central  nervous  system  and  also 
affects  a  number  of  peripheral  organs;  in  some  of  these  the  changes 
are  due  to  the  interruption  of  nerve  paths,  while  in  others  these  remain 
intact  under  atropine. 

Symptoms.— In  man  y|^  gr.  (0.6  mg.),  causes  some  dryness  of  the 
mouth  and  throat,  and  thirst;  the  skin  also  feels  dry,  and  the  heart  may 
be  accelerated  after  a  short  period  of  slowing.  Doses  of  ^V  gr.  (2.5  mgs.) 
are  followed  by  marked  dryness  of  the  skin  and  throat,  thirst,  difficulty 
in  swallowing  and  hoarseness  in  speaking.  There  is  often  nausea,  and 
in  some  cases  vomiting,  headache,  and  giddiness;  the  pupils  are  wider 
than  normal  and  the  sight  may  be  indistinct,  especially  for  near  objects. 
The  respiration  may  be  quicker  and  the  pulse  often  beats  at  one  hundred 
per  minute  or  more.  A  symptom  that  is  often  present,  though  by  no 
means  invariably  so,  is  redness  of  the  skin,  more  especially  of  the  head 
and  neck;  the  conjunctiva  may  also  be  congested.  After  larger  doses 
the  same  symptoms  are  observed,  but  are  soon  followed  by  others  of 
graver  import.  The  patient  can  no  longer  swallow,  although  suffer- 
ing from  intense  thirst,  the  heart  is  generally  extremely  rapid,  speech 
is  difficult  and  hoarse,  and  the  pupils  are  dilated  until  the  iris  almost 
disappears.  Restlessness  and  garrulity  point  to  an  increase  in  the 
irritability  of  the  brain;  the  patient  at  first  talks  in  a  perfectly  normal 
way  but  soon  becomes  confused,  begins  a  sentence  and  does  not  finish 
it,  often  bursts  into  laughter  or  sobs,  and  in  short  becomes  delirious 
and  eventually  maniacal.  Often  marked  tremor  of  different  muscles 
may  be  observed,  and  eventually  convulsions  set  in  and  may  be  the 
cause  of  death  through  the  failure  of  the  respiration.  As  a  general 
rule,  however,  the  stage  of  excitement  passes  into  one  of  depression, 
the  patient  sinks  into  a  sleep,  which  deepens  into  stu])or  and  coma, 
the  respiration  and  heart  become  slow,  weak  and  irregular,  and.deatii 
eventually  occurs  from  asphyxia. 

In  the  frog  the  injection  of  small  quantities  of  atropine  is  folh)wo<l 
by  a  period  of  depression  and  ])aralysis  of  tiic  p('rii)lioral  nerve  terniiuii- 
tions  resenibliiiii;  that  seen  uiicU'r  ciirara;  after  a  few  (hiys  there  suju'r- 


I 

I 


ATROPINE  317 

venes  a  stage  of  increased  reflex  excitability  and  tonic  convulsions 
indistinguishable  from  those  seen  under  strychnine.  This  stage  slowly 
passes  off  and  the  animal  again  becomes  normal. 

Action. — These  symptoms  in  man  and  other  mammals,  indicate 
stimulation  of  the  Central  Nervous  System  followed  by  depression. 
Those  observed  in  man  sometimes  resemble  those  seen  in  the  excite- 
ment stage  of  alcohol  poisoning,  and  it  has  been  suggested  that  in 
both  the  cause  is  rather  a  lessening  of  the  control  normally  exercised 
by  the  higher  powers  over  the  lower  motor  areas  than  a  true  stimula- 
tion of  the  latter.  But  this  is  shown  to  be  incorrect  by  the  fact  that 
in  atropine  poisoning  the  motor  area  is  more  easily  stimulated  by  the 
electric  current  than  normally.  The  stimulant  action  of  atropine 
is  also  seen  in  the  increased  reflex  response  to  irritation  of  the  skin, 
as  well  as  in  the  augmented  activity  of  the  centres  in  the  medulla. 
The  nervous  symptoms  under  atropine,  therefore,  arise  from  true 
stimulation  of  the  central  nervous  system,  but  they  are  wholly  dift'erent 
from  those  produced  by  strychnine,  because  the  latter  acts  more  espe- 
cially on  the  lower  parts  of  the  nervous  axis,  while  atropine  acts  more 
strongly  on  the  higher  divisions.  The  most  marked  symptoms  of 
strychnine  poisoning  arise  from  the  spinal  cord  and  medulla  oblongata, 
and  consist  in  increased  reflex  movements  and  convulsions,  while 
those  caused  by  atropine  are  rather  to  be  referred  to  the  brain,  and 
consist  in  increased  coordinated  movements,  such  as  talking  and 
delirium,  the  exaggerated  reflex  being  of  minor  importance. 

Atropine  differs  from  caffeine,  on  the  other  hand,  in  its  effect  on  the 
brain,  for  under  the  latter  the  psychical  functions  are  those  affected 
first  of  all.  It  would  seem  probable,  then,  that  each  of  these  three 
stimulates  the  whole  of  the  central  nervous  system  more  or  less,  but 
that  while  strychnine  acts  more  strongly  on  the  lower  divisions,  -the 
spinal  cord  and  medulla,  and  caffeine  on  the  highest  functions,  the 
psychical,  atropine  occupies  a  midway  position,  and  exercises  its  chief 
action  on  the  motor  divisions  of  the  brain.  These  are  rendered  so 
excitable  that  the  controlling  areas  can  no  longer  keep  them  in  check, 
and  an  increase  in  movement  occurs  somewhat  resembling  that  seen 
when  the  controlling  areas  are  depressed  by  alcohol.  The  stimulant 
action  spreads  downward  when  large  quantities  have  been  absorbed, 
and  involves  the  medulla  oblongata  and  spinal  cord,  so  that  symptoms 
resembling  those  seen  in  strychnine  poisoning  may  make  their  appear- 
ance. After  the  stimulation  has  lasted  some  time,  depression  sets  in 
and  may  go  on  to  complete  paralysis  of  the  central  nervous  system, 
which  is  fatal  to  mammals  through  cessation  of  the  respiration.  Even 
during  the  stimulation  stage  some  symptoms  of  depression  are  to  be  made 
out,  exactly  as  has  been  described  under  strychnine. 

The  peripheral  action  of  atropine  involves  a  nimiber  of  secretory 
glands,  organs  containing  unstriped  muscular  tissue,  and  the  heart. 

INIost  of  the  Secretions  are  decreased  by  the  application  of  atropine 
— salivary,  gastric,  pancreatic,  mucus,  and  sweat.  This  is  due,  not 
to  any  action  upon  the  secretory  cells,  but  to  the  failure  of  nervous 


318  SCBSTAXCES  ACTIXG  AFTER  ABSORPTIOX 

impulses.  It  has  been  investigated  most  carefully  in  the  salivary 
glands,  but  enough  work  has  been  done  on  the  others  to  show  that  the 
process  is  the  same  in  all.  The  .secretion  of  saliva  in  the  normal  animal 
seems  to  occur  only  when  impulses  reach  the  gland  cells  by  one  of  two 
paths — through  the  chorda  tympani,  or  through  the  cervical  sympathetic 
fibres.  If  the  chorda  t\-pani  be  divided  and  put  on  electrodes  and  a 
cannula  be  passed  into  Wharton's  duct,  a  rapid  flow  occurs  through  it 
on  stimulation  of  the  nerve,  which  ceases  or  is  very  much  diminished 
on  stopping  the  stimulation.  If  now  atropine  be  injected,  stimulation 
causes  no  increase  in  the  secretion,  and  atropine,  therefore,  seems  to 
paralyze  some  part  of  the  peripheral  secretory  apparatus.  The  chorda 
tympani  passes  through  ganglion  cells  on  its  way  to  the  gland  cells, 
and  the  impulses  might  be  hindered  in  their  passages  through  these,  as 
actually  occiu-s  imder  the  action  of  some  drugs.  (See  Nicotine.)  But 
this  is  not  the  explanation  of  the  inefficiency  of  chorda  stimulation,  as 
is  shown  by  the  fact  that  if  the  electrodes  be  pushed  into  the  hilus  of  the 
gland  so  as  to  stimulate  the  nerve  fibres  beyond  the  ganglia  no  secretion 
follows.  Another  explanation  would  be  that  the  gland  cells  themselves 
are  paralyzed  by  atropine,  but  this  is  shown  not  to  be  the  case,  for 
on  stimulating  the  s\Tnpathetic,  which  supplies  the  same  cells  as  the 
chorda  tympani.  the  usual  secretion  follows.  The  site  of  action  of  atro- 
pine, therefore,  seems  to  lie  between  the  gangHon  cells  on  the  course 
of  the  chorda  tjTnpani  and  the  secretory  cells,  that  is,  the  point  of 
attack  is  the  terminations  of  the  nerve  fibres  in  the  gland  cells.  The 
action  is  limited  to  certain  definite  terminations,  for  it  has  been  noted 
already  that  the  s\Tnpathetic  secretory  fibres  are  not  paralyzed,  and  it 
was  discovered  by  Heidenhain  that  the  vasodilator  fibres  of  the  chorda 
tjinpani  are  not  paralyzed  by  atropine.  Stimulation  of  the  nerve 
after  atropine  therefore  induces  no  secretion,  but  the  gland  becomes 
red  and  swollen,  and  the  blood  escapes  from  the  veins  in  larger  quantity 
and  in  spiui:s  in  the  same  way  as  in  the  unpoisoned  animal  under  chorda 
stimulation.  Atropine,  then,  seems  to  select  the  terminations  of  the 
secretory-  fibres  of  the  chorda  t\-mpani  for  paralysis  and  to  leave  all 
others  unaffected.  The  secretion  of  saUva  seems  to  occur  generally 
only  on  the  arrival  of  impulses  by  way  of  the  chorda  tympani.  so  that 
on  the  paralysis  of  its  terminations  the  secretion  ceases  entirely. 

In  the  same  way  the  other  glands  of  the  mouth,  throat,  nose  and  respira- 
tory passages  cease  secreting  after  atropine,  and  the  effect  is  the  char- 
acteristic dryness  of  the  mouth,  the  hoarseness  of  the  voice,  and  the 
thirst  and  difficulty  in  swallowing  complained  of  after  its  administration. 

The  secretion  of  the  gastric  juice  has  recently  been  shown  to  be 
diminished  or  entirely  arrested  by  atropine,  which  paralyzes  the 
terminations  of  the  secretory  fibres  of  the  pneumogastric  nerve  in  the 
stomach.  The  hydrochloric  acid  of  the  secretion  is  more  reduced 
than  either  the  pepsin  or  the  fluid  as  a  whole.  The  secretion  of  paii- 
creatic  juice  is  reduced  after  atropine,  and  stimulation  of  the  pneumo- 
gastric has  no  effect  on  it,  while  in  the  normal  animal  it  accelerates 
the  flow.     The  secretion  induced  by  the  specific  pancreatic  hormone. 


ATROl'lSE  319 

secretin,  continues,  showing  that  atropine  does  not  act  on  the  cells 
of  the  pancreas,  but  only  isolates  them  from  the  pneumogastric  nerve. 
But  as  the  formation  of  secretin  depends  on  the  passage  of  hydrochloric 
acid  into  the  duodenum,  and  this  is  lessened  by  the  action  on  the  gastric 
glands,  the  pancreatic  secretion  is  further  reduced  in  this  indirect  way. 
The  secretion  of  tears  is  diminished  by  atropine,  presumably  from 
the  interruption  of  the  nervous  connections  of  the  lachrymal  glands. 
The  hile  is  also  said  to  be  somewhat  lessened  by  atropine.  The  pro- 
duction of  sugar  from  the  glycogen  of  the  liver  has  been  recently  shown 
to  be  controlled  by  branches  of  the  coeliac  plexus,  but  these  have  no 
efTect  after  atropine,  so  that  the  terminations  of  the  nerv-es  in  the  liver 
cells  seem  to  be  paralyzed  also. 

The  same  paralysis  is  produced  in  the  terminations  of  the  ner\es  in 
the  siceat  glands.  Stimulation  of  the  sciatic  nerve  as  a  general  rule 
causes  perspiration  in  the  foot  of  the  cat  and  dog,  but  after  atropine 
this  effect  is  absent,  because  the  impulses  cannot  reach  the  cells  through 
the  paralyzed  terminations,  and  the  skin  therefore  becomes  dry  and 
hot.  The  local  apphcation  of  atropine  to  the  skin  has  no  effect  on  the 
sweat  secretion,  as  it  does  not  penetrate  to  the  glands.  The  secretion 
of  milk  is  not  materially  changed  by  atropine,  whether  the  alkaloid 
is  carried  to  it  by  the  blood  or  is  appHed  locally;  and  such  drugs  as 
increase  the  milk  secretion  (pituitary  extract)  are  not  antagonized  by 
atropine.  This  is  in  accord  with  the  physiological  observation  that 
the  mammary  gland  continues  to  secrete  after  all  its  nerves  have  been 
cut  and  allowed  to  degenerate;  in  other  words  the  mammary  secretion 
is  largely  independent  of  the  central  nervous  system. 

The  kidney  is  not  controlled  so  directly  by  ner^-e  influences  as  most 
of  the  glands,  and  atropine  causes  little  or  no  change  in  the  amount 
of  urine"  except  what  is  probably  the  indirect  result  of  the  arrest  of  the 
other  secretions.  The  secretion  of  lymph  is  not  altered  by  atropine, 
so  that  it  is  probably  not  controlled  by  nerves  in  the  same  way  as  the 
true  secretions. 

All  Organs  CJontaining  Unstriped  Muscle  (apart  from  the  arterial  waU) 
seem  to  be  altered  by  atropine.  Thus  the  movements  of  the  pupil 
and  cesophagus  (except  in  animals  in  which  these  consist  of  striped 
muscle),  stomach,  intestine,  bladder,  uterus,  spleen  and  thoracic  duct 
are  affected  by  atropine. 

The  dilatation  of  the  pupil  occm-s  on  internal  administration  as  well  as 
on  the  application  of  minute  quantities  locally,  and  is  due  to  paralysis 
of  the  myoneural  junctions  in  the  circular  muscle  of  the  iris.  This  is 
shown  by  the  fact  that  stimulation  of  the  motor  ocidi  ner^'e  or  of  the 
postganglionic  fibres  from  the  ciliary  ganglion  is  without  effect.  This 
limits  the  paralysis  to  the  periphery,  and  that  the  muscle  is  not  acted 
on  is  shown  by  its  reacting  to  electrical  stimulation.  The  local  nature 
of  the  action 'may  be  further  shown  by  carefully  applying  a  minute 
quantity  of  the  drug  to  one  side  of  the  cornea,  when  dilatation  of  one 
half  or  less  of  the  pupil  occurs,  the  rest  remaining  contracted.  The 
motor    oculi    (Fig.    26)    constantly    transmits  impulses    tlirough  the 


320 


SUBSTANCES  ACTING  AFTER  ABSORPTION 


ciliary  iier\es  to  the  sphincter  muscle  of  the  iris  and  keeps  the  pupil 
moderately  contracted,  and  when  these  impulses  can  no  longer  reach 
the  iris  owinti;  to  the  interruption  of  the  path,  the  sphincter  relaxes 
and  the  pupil  dilates.  The  contractile  substance  does  not  seem  to 
be  affected  by  the  ordinary  application  of  atropine,  but  if  strong  solu- 

FiG.  26 


Diagram  of  the  innervation  of  the  iris.  P,  a  fibre  of  the  motor  oculi  passing  from 
the  brain  to  the  ciliary  gangHon  (A''),  in  which  it  terminates  around  a  nerve  cell,  which 
sends  an  axis  cylinder  to  terminate,  M,  in  the  circular  fibres  of  the  iris.  R,  a  sympathetic 
nerve  fibre  issuing  from  the  lower  cervical  cord,  running  through  the  stellate  and  inferior 
cervical  ganglia  and  terminating  around  a  ganglion  cell  in  the  superior  cervical  ganglion, 
G.  The  axis  cylinder  from  this  nerve  cell  runs  to  the  iris  (passing  the  ciliary  ganglion) 
and  terminates,  C,  on  the  radiating  fibres.  M  is  the  point  acted  on  by  atropine  and 
muscarine.  N,N',  the  ganglion  cells,  is  the  seat  of  action  of  nicotine.  C,  the  terminations 
in  the  dilator  fibres,  that  of  cocaine  and  adrenaline. 

tions  be  continuously  applied,  it  may  be  paralyzed  by  it  as  by  many 
other  drugs.  Atropine  antagonizes  the  action  of  pilocarpine  in  the 
pupil  after  degeneration  of  the  motor  oculi,  and  the  receptor  for  these 
alkaloids  therefore  does  not  undergo  degeneration  and  must  be  situated 
in  the  muscle  between  the  nerve  ends  and  the  contractile  substance. 


The  conslrictor  muscle  is  constantly  opposed  by  dilator  fibres,  and  when 
the  former  is  llirown  out  of  activity  by  the  paralysis  of  the  terminations  of 
the  motor  oculi,  the  radiating  fibres  cause  an  active  dilatation.  If,  however, 
tlio  radiating  nuiscular  fibres  he  separated  from  their  iimorvating  centre  by 
section  of  the  cervical  sympathetic  nerve  in  the  neck,  they  also  cease  to  con- 
tract and  there  is  no  active  dilatation,  so  that  atropine  causes  less  widening 
of  the  pu])il  than  it  would  if  impulses  continued  to  reach  the  radiating  muscle. 


ATROPINE 


321 


After  the  Jipplicatiou  of  atropine  to  the  e3^e,  tlie  iris  often  relaxes  with  suffi- 
cient force  to  tear  weak  adhesions  to  the  lens,  and  if  the  iris  be  attach(Hl  at 
two  i)oints  to  the  lens,  atropine  causes  a  bow-shaped  dilatation  between  them, 
the  concavity  being  directed  inward.  The  dilatation  is  therefore  an  active 
movement,  accomplished  by  the  contraction  of  the  radiating  muscular  fil)res, 
but  these  are  not  put  in  motion  by  the  action  of  atropine  on  the  radiating 
muscles  of  the  iris,  or  their  nerves,  but  by  the  normal  impulses  descending 
from  the  central  nervous  system,  which  after  atropine  are  not  counterbalanced 
by  impulses  reaching  the  circular  fibres. 

The  dilatation  of  the  pupil  effected  by  atropine  is  not  quite  maxi- 
mal, for  stimulation  of  the  cervical  sympathetic  trunk  generally 
increases  it,  though  but  slightly.  It  differs  considerably  in  different 
animals,  being  more  complete  in  man,  the  dog  and  the  cat  than  in 
the  rabbit,  entirely  absent  in  birds  and  reptiles,  and  elicited  with  diffi- 
culty in  the  frog.  In  birds  and  reptiles  the  iris  consists  of  striped 
muscle  fibres,  and  accordingly  atropine  has  no  action  on  the  nerve 
terminations. 


Fig.  27 


Fig.  28 


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Charts  of  the  changes  in  the  accommodation  (pp)  and  in  the  pupil  (dd)  under  atropine. 
The  impairment  of  the  accommodation  and  the  widening  of  the  pupil  are  indicated  by 
downward  movements  of  the  lines,  while  the  return  to  the  normal  is  shown  by  an  upward 
movement.  In  Fig.  27  the  time  from  the  application  of  atropine  is  given  in  minutes  to 
show  the  beginning  of  the  action;  in  Fig.  28  the  time  is  in  hours  to  show  the  gradual 
recovery.     (After  Lewin  and  Guillery.) 


When  complete  dilatation  is  attained,  the  pupil  ceases  to  contract 
in  bright  light,  as  the  impulses  descending  from  the  central  nervous 
system  are  prevented  from  reaching  the  muscle,  although  the  rest  of 
the  reflex  arc  is  intact.  The  retina  is  unprotected  from  bright  light  and 
this  often  gives  rise  to  pain  and  discomfort  in  the  eyes  and  headache. 

Besides  the  dilatation  of  the  pupil,  a  further  result  of  the  applica- 
tion of  atropine  to  the  eye  is  the  paralysis  of  the  accommodation.  Near 
objects  are  no  longer  seen  clearly,  while  distant  ones  are  as  distinct 
as  formerly  or  may  be  even  more  distinct  in  some  eyes.  The  action 
is  here  again  on  the  myoneural  junction,  in  this  case  in  the  ciliary 
muscle.  On  local  application  the  relaxation  of  the  lens  occurs  later, 
21 


322 


SUBSTANCES  ACTING  AFTER  ABSORPTION 


., 


and  disappears  earlier  than  the  dilatation  of  the  pupil,  and  larger 
quantities  are  required  to  produce  it. 

The  intraocular  pressure  appears  to  be  unchanged  by  atropine  in  the 
normal  eye,  but  when  there  is  a  tendency  to  hypernormal  pressure, 
atropine  often  augments  it  considerably  whether  it  is  applied  locally 
or  is  carried  to  the  eye  by  the  circulation.  This  is  apparently  the 
indirect  result  of  the  dilation  of  the  pupil,  by  which  the  lymph  outflow- 
is  obstructed ;  in  the  normal  eye  this  is  not  sufficient  to  raise  the  pressure, 
but  in  eyes  in  which  the  outflow  is  already  deficient  the  additional 
hindrance  may  suffice  to  increase  the  tension  and  precipitate  an  attack 
of  glaucoma. 

The  bro)ichial  muscle  normally  contracts  when  the  pneumogastric 
nerve  is  stimulated,  but  makes  no  response  after  atropine,  which  par- 
alyzes the  myoneural  terminations;  the  sympathetic  fibres  which  inhibit 
the  bronchial  muscle  and  dilate  the  bronchi  are  unaffected  by  atropine. 

Fig.  29 


Movements  of  the  intestine.  At  P,  pilocarpine  causes  a  violent  tetanic  contraction, 
whifli  is  maintained  until  at  A  atropine  is  applied,  when  the  spasm  is  immediately 
relieved.     The  normal  pendulum  movements  continue  afterward.     (Magnus.) 

The  terminations  of  the  nerves  in  the  unstriped  muscle  of  the 
oosophaqus  are  affected  in  the  same  way  as  in  the  bronchial  muscle. 
A  curious  contrast  has  been  noted  by  Luchsinger  in  the  belnnior  of 
the  of'sophagus  in  rabbits  and  cats,  in  the  former  of  which  the  muscle 
is  striated,  while  in  the  latter  the  upper  part  is  striated,  the  lower 
is  vuistriatcd.  Atropine,  he  found,  paralyzes  the  AJigus  in  those  parts 
which  are  unstriped,  while  leaving  unallVcted  those  in  which  the  fibres 
are  strii)ed.  Exactly  the  opposite  occurs  after  curara,  which  ])aralyzes 
the  nerve  sui)ply  of  the  striped   nniscle.  while  l(>aviiig  the  unstriiied 

active.  •  i     • 

It  is  possible  that  the  didiculty  in  swallowing,  which  is  so  well 
marked  in  cases  of  poisoning  by  atropine,  may  be  <lue  in  i)art  to  the 


ATROPINE  323 

paralysis  of  the  motor  nerve,  but  it  is  generally  attributed  to  the 
absence  of  the  mucous  secretion  and  consequent  dryness  of  the  passages. 

Atropine  has  generally  a  sedative  effect  on  the  movements  of  the 
stomach  and  intestine,  though  vomiting  is  not  infrequently  observed 
in  cases  of  poisoning,  and  less  often  free  evacuation  of  the  contents 
of  the  bowel.  After  very  small  quantities  the  normal  peristalsis  is 
not  affected,  and  the  movement  induced  by  ordinary  doses  of  the  purga- 
tives is  not  arrested,  but  the  griping  pains  resulting  from  large  doses 
or  from  the  more  violent  purgatives  are  absent  or  less  marked  if  atro- 
pine is  given  along  with  them.  Similarly,  the  violent  peristaltic  and 
tetanic  contractions  seen  after  such  poisons  as  pilocarpine  and  mus- 
carine are  prevented  by  the  preliminary  injection  of  atropine. 

These  results  suggested  that  atropine  paralyzes  the  terminations  of 
some  of  the  extrinsic  nerves  of  the  stomach  and  bowel  in  the  same 
way  as  it  paralyzes  the  oculomotor  terminations  in  the  iris.  But  this 
proves  to  be  incorrect,  for  the  vagus  and  splanchnic  nerves  continue  to 
exert  their  ordinary  influence  after  atropine.  In  fact,  these  small 
doses  of  atropine  appear  to  arrest  only  certain  abnormal  violent 
forms  of  contraction,  and  as  they  do  this  without  interfering  with  the 
normal  peristalsis  and  without  interrupting  the  path  of  nervous  im- 
pulses from  the  brain  to  the  bowel,  it  must  be  accepted  that  these 
abnormal  forms  arise  from  some  mechanism  which  is  distinct  from 
that  presiding  over  the  ordinary  peristalsis,  and  which  does  not  lie  on 
the  path  of  the  nerve  impulses. 

This  action  on  abnormal  contractions  is  the  only  one  induced  by 
therapeutic  doses  of  atropine,  but  in  animal  experiments  large  quantities 
tend  to  increase  the  peristalsis  from  some  action  exerted  on  the  plexus 
of  Auerbach  (Magnus).  It  is  possible  that  this  increased  peristalsis 
may  account  for  the  vomiting  and  purging  sometimes  seen  in  cases  of 
poisoning.  Finally,  very  large  quantities  paralyze  the  muscle  fibres, 
but  this  probably  does  not  occur  in  the  intact  animal. 

Atropine  exercises  the  same  sedative  effect  on  the  movements  of 
other  organs  as  on  those  of  the  bowel.  Thus,  the  spleen,  uterus  and 
bladder  react  like  the  stomach  and  bowel,  several  poisons  failing  to 
induce  contractions  after  atropine,  while  stimulation  of  the  nerves 
continues  to  be  effective.  It  has  been  observed  frequently  in  cases  of 
poisoning  that  the  urine  is  ejected  soon  after  the  ingestion  of  the  poison, 
and  subsequently  there  is  a  desire  to  micturate  without  the  ability 
to  do  so.  The  rhythmical  contractions  of  the  ureters  are  said  to  be 
accelerated  by  small  doses,  but  to  be  slowed  and  arrested  by  larger 
amounts. 

Atropine  paralyzes  the  Inhibitory  Terminations  of  the  Vagus  in  the 
Heart,  and  stimulation  of  this  nerve  therefore  causes  no  changes  in 
the  pulse  after  its  administration.  Nicotine  in  large  doses  also  removes 
the  inhibitory  power  of  the  vagus,  but  acts  on  a  different  part  of  the 
nerve,  namely,  on  the  ganglia.  That  atropine  does  not  act  here  but 
on  the  terminations  has  been  shown  by  a  number  of  observations. 
Thus,  in    the   normal   frog's   heart,  and   even   after   paralysis  of  the 


324 


SUBSTANCES  ACTING  AFTER  ABSORPTION 


ganglia  on  the  course  of  the  vagus,  electrical  stimulation  of  the  venous 
sinus  causes  slowing  and  standstill  of  the  heart,  because  the  stimulus 
reaches  the  postganglionic  nerve  fibres  (Fig.  24,  p.  306);  but  after 
atropine,  no  slowing  follows  stimulation  of  the  sinus.  Again,  several 
drugs  stimulate  the  ends  of  the  vagus  in  the  heart  and  act  on  parts 
in  which  no  ganglia  exist,  but  these  drugs  have  no  effect  whatever 
after  atropine.  Small  quantities  of  atropine  have  no  further  action 
on  the  heart  than  the  paralysis  of  the  inhibitory  nerve  ends.  The 
terminations  of  the  accelerator  nerve  are  unaffected,  exactly  as  the 
terminations  of  the  sympathetic  in  the  salivary  glands,  and  the 
heart  muscle  is  neither  stimulated  nor  depressed.  The  heart  is  there- 
fore placed  in  the  same  position  as  if  the  vagus  were  divided  in  the 
neck,  and,  accordingly,  it  is  accelerated  in  some  animals,  while  in  others 
the  rhythm  is  unchanged.  In  the  dog  there  is  marked  quickening 
of  the  heart  after  atropine,  because  normally  impulses  are  constantly 


Fig.  30 


Tracings  of  the  ventricle  (lower)  and  auricle  (upper)  of  the  dog's  heart.  During 
systole  the  levers  moved  upward;  during  diastole,  downward.  At  A,  the  heart  was 
normal;  at  B,  the  inhibitory  fibres  were  stimulated  electrically,  and  this  was  continued 
throughout  the  tracing.  The  ventricular  rhythm  became  slow  and  irregular,  while  the 
auricle  stood  still  in  diastole.  At  C,  atropine  sulphate  was  injected  into  a  vein,  and  at 
D  the  effects  of  the  inhibition  began  to  pass  off,  although  the  stimulation  was  continued. 

transmitted  from  the  inhibitory  centre  in  the  medulla,  and  these  pre- 
vent the  heart  from  beating  as  rapidly  as  it  would  if  freed  from  the 
nervous  control.  In  the  cat  the  tone  of  the  vagus  is  less,  and  the 
changes  produced  by  atropine  are  correspondingly  smaller,  while  in 
the  rabbit  and  frog  there  is  generally  no  inhibitory  retardation  of  the 
heart,  and  atropine  therefore  produces  little  change.  In  man  the 
effects  vary  considerably  with  the  age  of  the  patient.  The  inhibitory 
fibres  seem  almost  inactive  at  birth,  but  their  tone  increases  with  age 
up  to  25-35  years,  and  from  this  time  lessens  again  and  is  very  slight 
in  old  age.  Atropine  does  not  quicken  tlie  heart  in  the  newborn  child, 
but  up  to  about  .'50  the  acceleration  increases  with  the  age,  and  from 
this  point  onwards  it  lessens  again  until  the  heart  is  accelerated  by 
only  4-5  beats  jxt  minute  in  i)atients  between  80-00  years.  Along 
witli  the  acceleration  of  the  pulse  the  other  cM'ects  of  vagus  section 
are  also  produced— increase  in  the  extent  of  s\stole,  decrease  in  the 
diastole  and  augmentation  of  the  output  of  the  heart  per  minute.  . 


i 


ATROPINE  325 

Stimulation  of  the  vagus  causes  no  retardation  of  the  pulse  after  atropine, 
but,  on  the  contrary,  is  not  infrequently  followed  by  acceleration  from  the 
presence  of  accelerator  fibres  which  are  not  affected  by  atropine. 

Large  quantities  of  atropine,  besides  paralyzing  the  vagus,  weaken  and 
depress  the  heart  muscle,  and  the  contractions  consequently  become  slower  and 
weaker  and  the  output  of  the  heart  is  less  than  normal.  Even  therapeutic  doses 
injected  hypodermically  in  man  slow  the  pulse  for  a  short  time,  apparently 
from  direct  action  on  the  heart  muscle;  the  first  effect  is  thus  a  fall  in  the 
pulse  rate  followed  by  marked  acceleration. 

The  peripheral  action  of  therapeutic  doses  of  atropine  is  due  to  its 
paralyzing  receptors  in  a  number  of  organs.  Some  of  these  are  nor- 
mally put  in  action  by  nerve  impulses,  which  they  transmit  to  the 
contractile  or  secretory  cells,  and  their  paralysis  by  atropine  leads  to 
the  failure  of  part  of  the  nervous  control  of  the  organ  (many  glands, 
pupil,  bronchial  muscle,  oesophagus,  and  heart).  In  other  organs  the 
receptors  do  not  lie  in  the  path  of  nerve  impulses  and  their  paralysis 
by  atropine  therefore  does  not  affect  the  nervous  control  of  these 
organs  (muscle  of  stomach,  intestine,  spleen,  uterus,  and  bladder). 
The  effects  of  atropine  on  these  organs  is  in  fact  only  detected  by  the 
cessation  of  unusual  movements  induced  by  certain  poisons  and  by 
some  pathological  conditions  (see  also  muscarine  and  pilocarpine, 
p.  338).  The.  organs  thus  affected  receive  their  innervation  from 
the  autonomic  system,  some  of  them  from  the  craniosacral  division, 
some  others  from  the  sympathetic;  atropine  cannot  be  said  to  affect 
either  of  these  divisions  exclusively,  but  its  action  on  the  myoneural 
junctions  of  the  craniosacral  division  is  more  prominent  than  that  on 
the  sympathetic. 

The  voluntary  Muscles  are  not  directly  affected  by  atropine.  An 
action  similar  to  that  of  curara  is  seen  in  the  frog  under  large  doses, 
and  evidence  of  a  similar  action  in  mammals  is  offered  by  the  fact 
that  the  twitching  induced  by  physostigmine  through  its  action  on 
the  myoneural  junctions  is  antagonized  by  atropine;  but  no  true  curara 
action  is  induced   by   atropine   in   mammals. 

The  terminations  of  the  Sensory  Nerves  are  depressed  by  its  local 
application.  Thus,  when  atropine  is  applied  to  an  irritated  surface  of 
the  skin  or  to  a  mucous  membrane,  numbness  is  produced  and  the  sen- 
sation of  pain  is  lessened ;  no  such  effect  occurs  when  atropine  ointment 
is  rubbed  on  the  unbroken  skin  and  the  local  anaesthetic  effect  is  not 
elicited  by  its  internal  administration. 

Circulation. — The  changes  in  the  circulation  under  atropine  arise 
for  the  most  part  from  the  changes  in  the  heart.  The  blood-pressure 
often  falls  for  a  few  minutes  at  first  from  the  direct  action  on  the  heart 
muscle  and  then  rises  above  the  normal  from  the  acceleration  when  this 
is  marked.  But  the  rise  in  pressure  from  the  acceleration  is  not  great 
unless  there  is  unusual  activity  of  the  inhibitory  mechanism  previously. 
There  is  no  evidence  that  the  vasoconstrictor  centre  in  the  medulla 
is  excited  by  atropine,  and  although  concentrated  solutions  of  atropine 
perfused  through  the  vessels  cause  them  to  dilate  from  action  on  their 


326  SUBSTANCES  ACTING  AFTER  ABSORPTION 

walls,  this  does  not  occur  in  the  living  animal.  Very  large  amounts 
of  atropine  depress  the  heart  and  consequently  the  blood-pressure  falls; 
the  respiration  fails  in  cases  of  poisoning  before  the  heart  is  seriously 
injured.  In  i)oisoning  there  is  often  flushing  of  the  skin  of  the  head 
and  neck  and  a  rash  resembling  that  of  scarlet  fever,  and  these  have 
been  regarded  as  due  to  dilatation  of  the  arterioles  from  stimulation  of 
the  vasodilator  centre;  the  flush  is  said  to  disappear  on  section  of  the 
cer^•ical  sympathetic  cord,  which  would  suggest  its  central  origin.  The 
rash  usually  disappears  after  a  few  hours,  but  is  sometimes  followed 
in  a  day  or  two  by  desquamation. 

The  action  of  atropine  on  the  Respiration  has  been  the  subject  of 
much  discussion  in  recent  years.  It  is  sometimes  slower  at  first  but 
then  becomes  quicker,  and  the  amount  of  air  inspired  per  minute  is 
considerably  increased  from  stimulation  of  the  respiratory  centre. 
After  large  doses  this  quickened  breathing  is  frequently  interrupted 
by  convulsive  movements,  and  such  an  interruption  often  proves  to 
be  final.  It  if  returns,  the  movements  become  shallower  and  slower 
in  the  stage  of  depression  of  the  nervous  centres,  and  the  failure  of  the 
respiration  is  the  cause  of  death  in  fatal  cases  of  poisoning. 

Atropine  often  induces  a  marked  rise  in  Temperature,  the  cause  of 
which  cannot  be  said  to  be  definitely  known.  According  to  Ott  the 
dissipation  of  heat  is  increased,  but  the  heat  formation  undergoes  a 
still  greater  augmentation.  This  seems  to  be  independent  of  the  cir- 
culatory changes  and  also  of  the  convulsions,  and  is  attributed  by  him 
to  direct  action  on  the  heat  centres  of  the  brain. 

Distribution  and  Excretion. — Atropine  is  rapidly  absorbed  and  may 
be  found  in  most  organs.  It  is  excreted  in  the  urine  in  man  and  most 
animals,  partly  as  unchanged  atropine,  partly  broken  up  into  tropine; 
from  a  third  to  a  half  of  that  ingested  reappears  in  the  urine,  and  traces 
have  been  found  in  the  milk  and  also  in  the  foetal  blood.  The  rest  of 
the  atropine  undergoes  oxidation  in  the  body,  but  it  is  not  determined 
where  this  destruction  occurs  except  in  the  case  of  the  rabbit  where 
it  seems  to  be  rapidly  decomposed  by  ferment  action  in  the  blood;  the 
blood  of  man,  the  dog  and  many  other  animals  does  not  seem  to  possess 
this  property. 

Tolerance. — ^Nlost  animals  withstand  much  larger  quantities  of 
atropine  than  man,  and  an  especial  degree  of  tolerance  is  met  with 
in  the  herbivora;  rabbits,  for  example,  may  be  fed  for  weeks  on  bella- 
donna leaves  without  showing  any  symj^toms;  this  is  undoubtedly 
the  result  of  the  active  decomposition  of  the  alkaloid  which  occurs  in 
their  serum.  It  has  also  been  observed  that  the  action  of  atropine  on 
the  heart  and  other  organs  passes  off  more  quickly  in  rabbits  than  in 
other  animals  and  this  again  arises  from  the  atroj^ine  being  destroyed 
so  rapidly.  A  certain  degree  of  tolerance  may  also  be  acquired  by  other 
animals  through  the  continued  administration  of  atropine,  which  ceases 
to  elicit  the  symptoms  from  the  central  nervous  system  in  the  doses 
previously  sufficient  and  later  seems  to  have  a  weaker  and  shorter  action 
on  the  perij)heral  organs. 


ATROPINE  .  327 

Hyoscyamine  is  rarely  obtainable  in  pnre  form,  as  it  is  almost  always 
mixed  with  atropine,  into  which  it  changes  when  kept  in  solution  and 
j)erhaps  even  when  dry.  It  paralyzes  the  same  peri])heral  mechanisms 
as  atropine,  but  acts  almost  exactly  twice  as  strongly  on  them.  Its 
action  on  the  central  nervous  system  in  mammals  resembles  that  of 
atropine  and  the  fatal  dose  is  the  same,  but  in  the  frog  it  has  less  ten- 
dency to  cause  convulsions.  No  narcotic  influence  is  exercised  on 
either  frogs  or  mammals;  the  belief  that  it  induces  sleep  is  founded 
on  obser\'ations  in  which  hyoscine  was  mixed  with  the  hyoscyamine 
employed. 

The  action  of  atropine,  as  has  been  stated,  is  compounded  of  that  of  natural, 
or  la^vorotary,  hyoscyamine  with  that  of  its  dextrorotary  isomer.  The  latter 
does  not  exist  free  in  nature  and  possesses  little  or  no  action  on  the  nerve 
terminations,  while  it  stimulates  the  spinal  cord  of  the  frog  more  than  either 
atropme  or  hyoscyamine.  The  peripheral  action  of  atropine  i§  thus  due  to 
its  containing  hyoscyamine,  and  as  a  grain  of  atropine  contains  only  half  a 
grain  of  hyoscyamine  the  former  naturally  exercises  only  half  the  effect  of  a 
grain  of  hyoscyamine.  On  the  other  hand,  the  half  grain  of  dextrorotary 
hyoscyamine  in  a  grain  of  atropine  is  almost  inert  on  the  nerve  terminations, 
but  exercises  the  same  effect  on  the  central  nervous  system  as  its  Isevorotary 
complement.  Atropine  thus  acts  on  the  central  nervous  sj^stem  in  mammals 
in  the  same  strength  as  hyoscyamine,  but  only  half  as  strongly  in  the  periphery. 

Scopolamine,  or  Hyoscine,  resembles  atropine  closely  in  its  peripheral 
action,  except  that  it  passes  off  more  quickly.  The  inhibitory  termina- 
tions in  the  heart  are  paralyzed;  but  the  therapeutic  dose  in  man 
is  too  small  to  elicit  this  effect,  and  the  pulse  is  therefore  unaltered  in 
rate  or  may  be  slower,  owing  to  the  hypnotic  action.  Applied  to  the 
conjunctiva  it  produces  mydriasis  and  loss  of  accommodation  more 
quickly  than  atropine,  but  for  a  much  shorter  time;  pure  hyoscine  acts 
about  twice  as  strongly  on  the  nerve  terminations  as  atropine,  or  about 
equally  strongly  with  hyoscyamine.  The  effects  on  the  central  nervous 
system  present  the  greatest  divergences  from  those  described  under  atro- 
pine, for  the  characteristic  stimulation  is  absent  in  the  great  majority 
of  cases.  As  a  general  rule,  scopolamine  produces  a  marked  sensation 
of  fatigue  and  drowsiness,  the  patient  moves  about  less  and  speaks  less, 
and  a  condition  in  no  way  dissimilar  to  the  natural  sleep  follow^s.  In 
many  cases,  however,  a  short  stage  of  excitement  with  giddiness,  un- 
certain movements  and  difficult  and  indistinct  speech  precedes  sleep, 
and  occasionally  symptoms  exactly  resembling  those  produced  by 
atropine  follow  the  administration  of  hyoscine,  especially  if  large  doses 
are  employed.  Sleep  generally  lasts  from  5-8  hours,  and  the  patient 
may  then  remain  quiet  for  several  hours  longer.  As  a  general  rule, 
after  small  doses  no  confijsion  is  complained  of  on  awakening,  but 
dryness  of  the  throat  and  thirst  are  often  present.  Larger  doses  do  not 
cause  deeper  sleep  but  give  rise  to  delirium  and  excitement  resembling 
those  following  atropine. 

In  one  or  two  cases  collapse  has  been  observed  after  scopolamine. 
The  respiratory  centre  does  not  seem  to  be  stimulated  as  by  atropine, 
the  respiration  generally  becoming  slower  from  the  beginning. 


328  SUBSTANCES  ACTING  AFTER  ABSORPTION 

In  the  k)wer  mammals  scopolamine  reduces  the  excitability  of  the 
motor  areas  as  tested  by  electric  shocks,  while  the  reflex  excitability 
in  the  frop;  is  not  increased  as  by  atropine.  Ilyoscine  appears  to  be 
excreted  or  destroyed  in  the  tissues  much  more  rapidly  than  atropine, 
for  its  effects  last  a  shorter  time.  ♦ 

The  action  of  hyoscine,  then,  seems  to  correspond  with  that  of  atro- 
pine, save  that  the  central  nervous  system  is  here  depressed,  while  the 
action  on  the  peripheral  nerve  ends  is  stronger.  It  depresses  the  brain 
in  very  .small  quantities,  ^  mg.  (y^  gr.)  being  generally  sufficient  to 
cause  sleep.  It  does  not  seem  to  be  so  dangerous  as  the  others  of  the 
series,  for  a  dose  of  5  mgs.  (yV  gr.)  has  been  recovered  from  in  man, 
and  over  half  a  gramme  (7^  grs.)  administered  to  a  small  cat  did  not 
kill  the  animal.  A  certain  degree  of  tolerance  is  produced  after  repeated 
use,  so  that  the  dose  has  to  be  increased  after  a  week  or  two. 

Hyoscine  is  much  less  reliable  as  a  hy])notic  than  morphine  or  the 
members  of  the  chloral  group.  It  is  most  eft'ective  when  sleep  is  pre- 
vented by  motor  excitement,  and  the  sleep  seems  to  arise  from  the 
relief  of  this  condition  and  not  from  depression  of  the  consciousness. 

Hyoscine  is  la'vorotary  to  polarized  light;  the  racemic  form,  which  is  often 
present  in  conunercial  hyoscine,  acts  only  one-half  as  strongly  on  the  per- 
ipheral organs,  because  in  it  the  Isevorotary  alkaloid  is  mixed  with  the  dextro- 
rotary  isomer,  which  is  almost  inactive.  Tihe  cerebral  action  is  equal,  however, 
in  the  two  forms. 

The  other  natural  alkaloids  have  been  less  carefully  examined  than 
the  three  foregoing  and  possess  no  therapeutical  interest. 

Among  the  artificial  tropeines  only  one  has  received  much  attention 
at  the  hands  of  either  experimental  or  practical  therapeutists.  This 
is  Homatropine,  a  compound  of  tropine  and  mandelic  acid,  which  re- 
seml)les  atropine  in  its  action,  but  is  much  less  poisonous.  When 
applied  to  the  eye,  it  dilates  the  pupil  almost  as  rapidly  as  atropine, 
but  less  completely,  and  the  action  passes  off  much  sooner.  It  has  less 
tendency  to  increase  the  intraocular  tension  than  atropine  owing  to  its 
shorter  action. 

Methylatropine  or  Eumydrine,  an  artificial  compound  of  atropine, 
seems  to  take  a  place  intermediate  between  atropine  and  homatropine, 
being  weaker  than  the  former  but  more  active  than  the  latter.  It  has 
been  used  to  some  extent  in  opthalmology. 

The  other  tropeines  vary  in  their  action  on  the  lower  animals,  many  of  them 
failing  to  act  on  the  peripheral  organs,  while  others  have  the  peripheral  action 
of  atropine  but  in  a  weaker  degree;  tlie  compounds  of  tropine  with  the  acids 
of  the  methane  series  possess  much  less  of  the  peripheral  atropine  acti()n  than 
the  otlieis.  It  was  formerly  believed  that  even  the  comjwunds  with  the 
aromatic  acids  were  devoid  of  tliis  action  imless  the  acid  jiossessed  a  hydroxyl 
grou]),  hut  tliis  general  statement  has  hi-en  shown  to  be  erroneous  by  (Jottlieb's 
work.  A  considerable  variation  also  exists  in  the  effects  of  the  tn)i)eines  on  the 
central  nervous  system,  some  causing  excitement  like  atropine,  while  others 
act  as  depressants  and  thci'cforc  I'cscinhlc  hyoscine. 


ATROPINE  329 

Tropine  itself  is  a  weakly  toxic,  basic  substance,  which  in  large  (luantities 
stimulates  the  frog's  heart,  but  does  not  paralyze  the  vagus  nor  the  oculomotor 
terminations  on  local  a.i)plication.  After  the  injection  of  large  ciuantities, 
dilatation  of  tlu>  pupil  has  lieen  observed,  it  is  true,  but  this  does  not  seem  to  be 
of  the  same  origin  as  that  produced  by  atropine. 

Some  artihcial  scopoleincs  have  been  found  devoid  of  action  on  the  nerve  ends 
in  the  pupil  and  heart  and  on  the  salivary  secretion.  They  possess  a  certain 
stimulant  effect  on  the  heart  muscle  like  some  of  the  artificial  tropeines,  and  all 
produce  more  or  less  depression  of  the  central  nervous  system  and  narcosis. 

The  action  of  the  Crude  Drugs  is  very  similar  to  that  of  the  active 
principles  already  discussed.  The  peripheral  action  of  all  of  them  is 
therefore  almost  identical  in  kind,  though  varying  in  degree.  In  con- 
sidering their  efTects  on  the  central  nervous  system  it  must  be  remem- 
bered that  those  containing  much  atropine  are  more  stimulant,  those 
with  hyoscine  more  sedative.  But  as  the  relative  amount  of  the  different 
alkaloids  changes  with  various  conditions  such  as  the  age  of  the  plant 
and  the  methods  of  preparation,  it  is  obvious  that  accurate  results  can 
be  obtained  only  by  the  use  of  the  pure  principles.  Even  when  a 
preparation  is  accurately  standardized  in  the  content  of  alkaloids, 
as  in  the  U.  S.  P.  and  B.  P.,  its  power  may  vary  very  widely  according 
to  the  proportion  of  Isevorotary  alkaloid  (hyoscyamine)  to  racemic 
(atropine). 

Preparations. 

U.  S.  P. — Belladonnae  Folia,  the  leaves  of  Atropa  Belladonna,  containing 
0.35  per  cent,  of  mydriatic  alkaloids.    Dose,  0.065  G.  (1  gr.). 

ExTRACTUM  Belladonna  Foliorum  (1.4  per  cent.),  0.01  G.  (!  gr.). 

TiNCTURA  Belladonnae  Foliorum  (0.035  per  cent.),  0.5  c.c.  (8  mins.). 

Emplastrum  Belladonna  (0.4  per  cent,  of  alkaloids). 

Belladonnae  Radix,  the  root  of  Atropa  Belladonna,  containing  0.5  per  cent, 
of  alkaloids.    Dose,  0.045  G.  (f  gr.). 

LiNiMENTUM  Belladonna  (nearly  0.5  per  cent.),  containing  camphor. 

Hyoscyamus,  the  leaves  of  Hyoscyamus  niger,  henbane  (0.08  per  cent,  of 
alkaloids).     Dose,  0.25  G.  (4  grs.). 

ExTRACTUM  Hyoscyami  (0.3  per  cent,  of  alkaloids),  0.065  G.  (1  gr.). 

TiNCTURA  Hyoscyami  (0.007  per  cent,  of  alkaloids),  1  c.c.  (15  mins.). 

Stramonium,  the  dried  leaves  of  Datura  Stramonium  (0.35  per  cent,  of 
alkaloids).     Dose,  0.065  G.  (1  gr.). 

Extradum  Stramonii  (1.4  per  cent,  or  alkaloids),  0.01  G.  (^  gr.). 

Tinctura  Stramonii  (0.03  per  cent,  of  alkaloids),  0.5  c.c.  (8  mins.). 

Scopola,  the  dried  rhizome  of  Scopola  carniolica  (0.5  per  cent,  of  alkaloids). 
Dose,  0.045  G.  (|  gr.). 

B.  P. — Belladonnae  Folia,  the  fresh  leaves  and  branches  of  Atropa  Belladonna, 
containing  0.3  per  cent,  of  alkaloids. 

Belladonnae  Radix,  the  root  of  Atropa  Belladonna. 

ExTRACTUM  BELL.1DONNA  SiccuM  (1  per  Cent,  of  alkaloids),  |-1  gr. 

TiNCTURA  Belladonna  (0.035  per  cent,  alkaloids),  5-15  mins. 

LiNiMENTUM  Belladonna  (0.375  per  cent.),  with  camphor. 

Emplastrum  Belladonna  (0.25  per  cent.). 

Hyoscyami  Folia,  the  fresh  leaves,  flowers  and  branches  of  Hyoscyamus 
niger,  henbane. 

Extradum  Hyoscyami  (0.3  per  cent,  alkaloids),  2-8  grs. 

Tindura  Hyoscyami,  ^-1  fl.  dr. 

Stramonii  Folia,  the  dried  leaves  of  Datura  Stramonium. 

Tinctura  Stramonii,  5-15  mins. 


330  SUBSTANCES  ACTING  AFTER  ADSORPTION 

Alkaloids. 

AtuopiN/E  Sulphas  (U.  S.  P.,  B.  P.),  a  white  crystalline  powder,  with  a 
very  bitter  taste,  soluble  in  water  and  alcohol.  Dose,  0.0004  G.  di^u  gr.); 
B.  P.,  ,•„-,,'„  gr. 

Oleatutn  Atropince  (U.  S.  P.),  2  per  cent. 

Liquor  Atropince  Sidphatis  (B.  P.),  1  per  cent.,  ^-1  min. 

Lamella'.  Atropince  (B.  P.),  gelatin  discs,  each  containing  .„'o„  gr.  of  atropine 
sulphate. 

Hyoscyamine  is  not  procurable  in  even  approximately  pure  form  and  might 
well  be  dispensed  with,  as  it  offers  no  advantages  over  atropine.  The  sulphate 
and  hvdrobromide  have  been  used  in  the  same  dose  as  atropine. 

Hyoscin,e  Hydrobromidum  (U.  S.  P.,  B.  P.),  (C,7H2iN04HBr,3H20),  the 
hydrobromide  of  hj'oscine  or  scopolamine.  It  is  obtained  from  hyoscyamus, 
scopola  and  other  Solanacea?,  and  forms  colorless,  transparent  crystals  with  an 
acrid,  bitter  taste,  and  is  verv  soluble  in  water,  less  so  in  alcohol.  0.5  mg. 
{jU  gr.);  B.  P.,  ,hcrd^  gr.  " 

Scopolamince  Hydrohromidum  (U.  S.  P.)  is  identical  with  Hyoscine  hydro- 
bromide. 

HoMATROPiN^  Hydrobromidum  (U.  S.  P.,  B.  P.),  (Ci6H2iN03HBr),  the 
hydrobromide  of  an  alkaloid  prepared  from  tropine  by  condensation  with 
mandeUc  (oxytoluic)  acid,  a  white  crystalline  powder  soluble  in  6  parts  of 
cold  water. 

Lamellx  Homatropince  (B.  P.),  gelatm  discs,  each  weighing  J^  gr.  and 
containing  yIui  gr-  of  homatropine  hydrobromide. 

Methylatropince  Nitras  or  Eumydrin  (unofficial)  an  alkaloid  prepared  from 
atropine,  forms  a  white  crystalline  salt  readily  soluble  in  water.  Dose  1-3  mg. 
U^h  gr.). 

Therapeutic  Uses. — The  numerous  changes  produced  by  atropine  and 
its  congeners  on  the  organism  would  indicate  for  them  a  very  wide 
sphere  of  usefulness  were  it  possible  to  elicit  their  action  on  one  organ 
without  affecting  others,  and  this  difficulty  may  perhaps  be  overcome 
in  the  future,  when  the  different  individuals  of  the  series  have  been 
more  carefully  compared,  and  new  tropeines  and  other  modifications  of 
the  tropine  radicle  are  available  in  therapeutics. 

The  peripheral  action  of  the  whole  series,  as  far  as  it  is  at  present 
known,  is  so  uniform  that  any  member  might  be  used  to  elicit  it,  but 
the  only  one  that  has  come  into  general  use  for  its  peripheral  effects 
is  atropine.  The  purposes  for  which  atropine  is  employed  may  be 
divided  into  groups  as  follows: 

To  Arrest  or  Lessen  Secretions. — In  rare  cases  of  excessive  salivation 
atropine  has  proved  of  service,  but  it  is  much  more  frcc[uently  used  to 
lessen  the  perspLration,  especially  in  the  later  stages  of  phthisis.  For 
this  purpose  comparatively  small  quantities,  such  as  I  mg.  {ir^-^^  gr.) 
given  by  the  mouth  or  hypodermically,  are  generally  sufficient,  or  the 
extract  or  tincture  of  belladonna  may  be  used  instead;  eumydrin  has 
also  been  employed  for  this  purpose  in  somewhat  larger  doses  than 
atropine.  In  local  sweating,  atropine  is  often  appHed  locally  in  the  form 
of  an  ointment,  liniment,  or  plaster,  although  Tappeiner  has  found  that 
it  has  no  effect  when  thus  employed.  It  is  also  used  to  arrest  the  secre- 
tion of  the  viillc,  a  belladonna  i)laster  being  strapped  over  the  gland.  It 
seems  ])r()l)al)lc  that  this  acts  merely  as  a  mechanical  sui)i)ort  and  that 


ATROPINE  331 

the  same  result  would  follow  the  application  of  simple  adhesive  plaster 
without  atropine. 

To  Paralyze  the  Cardiac  Inhibitory  Terminations. — For  this  purpose 
a  slightly  larger  ciuantity  is  required  than  is  necessary  to  stop  the 
secretions,  and  the  administration  of  sufficient  atropine  to  paralyze 
the  vagus  (1  mg.)  therefore  involves  unpleasant  dryness  of  the  throat 
and  difficulty  in  swallowing.  In  cases  where  slowing  of  the  heart 
tends  to  be  dangerous  in  itself,  more  especially  in  poisoning  with 
muscarine,  pilocarpine  and  their  allies,  atropine  is  indicated.  _  It  may 
also  be  used  for  diagnostic  purposes,  to  find  if  bradycardia  is  due  to 
disease  of  the  heart  muscle  or  to  inhibition.  It  may  be  repeated  here 
that  the  resultant  quickening  is  much  less  in  old  than  in  middle-aged 
people,  and  it  is  said  that  in  many  cases  of  old  aortic  lesion  the  adminis- 
tration of  atropine  is  followed  by  little  or  no  acceleration.  Some  forms 
of  intermission  of  the  pulse  are  due  to  unusual  activity  of  the  inhibitory 
apparatus,  and  these  may  be  remedied  by  atropine;  but  this  inter- 
mission possesses  little  importance,  and  seems  to  require  no  therapeutic 
treatment.  Atropine  may  be  used  to  diagnose  it  from  the  more  sig- 
nificant forms  present  in  organic  disease  of  the  heart.  The  use  of  atropine 
to  paralyze  the  vagus  terminations  before  the  administration  of  an 
anaesthetic  has  been  discussed  already.     (See  p.  218.) 

To  Paralyze  the  Terminations  of  the  Motor  Nerves  in  the  Iris  and  Ciliary 
Muscles.— It  is  used  for  this  purpose  largely  in  ophthalmology  as  a 
means  of  diagnosis  and  of  treatment,  and  the  precise  conditions  in 
which  it  is  indicated  may  be  treated  better  in  text-books  on  this  sub- 
ject than  here.  For  these  objects,  solutions  of  the  alkaloidal  salts  are 
generally  applied  to  the  conjunctiva,  when  enough  of  the  alkaloid 
passes  into  the  eye  by  a  process  of  imbibition  to  produce  marked  local 
effects  without  affecting  more  distant  organs.  In  order  to  dilate  the 
pupil,  extremely  dilute  solutions  are  used;  a  few  drops  of  a  solution 
of  one  in  1,000,  or  even  of  one  in  10,000  are  quite  sufficient.  Much 
stronger  solutions  are  required  to  paralyze  the  accommodation,  and  as 
a  general  rule  1  per  cent,  is  used.  These  strong  solutions  produce 
complete  paralysis  in  1-1|  hours,  and  the  accommodation  does  not 
recover  completely  until  after  5-7  days,  while  the  pupil  may  not 
regain  its  normal  size  for  10-14  days.  The  application  of  even 
weaker  atropine  solution  renders  the  sight  imperfect  for  an  incon- 
veniently long  period,  and  hyoscine  and  homatropine  are  therefore 
much  used  in  its  stead.  The  symptoms  produced  by  a  1  per  cent, 
solution  of  homatropine  pass  oflf,  or  at  any  rate  become  very  much  less 
marked  in  the  course  of  36  hours.  These  are  consequently  preferable 
for  diagnostic  purposes,  while  atropine  is  rather  to  be  used  where  it 
is  desirable  to  produce  a  paralysis  of  longer  duration,  as  in  various 
inflammatory  conditions  of  the  iris  or  cornea.  Atropine  is  also  pref- 
erable where  complete  paralysis  of  the  accommodation  is  necessary,  as 
homatropine  often  fails  to  efi'ect  this.  Atropine  and  its  congeners 
are  contraindicated  where  there  is  any  suspicion  of  glaucoma,  as, 
owing  to  their  action  on  the  intraocular  pressure,  they  may  cither 
aggravate  the  disease  already  present  or  precipitate  an  acute  attack. 


332  SUBSTANCES  ACTING  AFTER  ABSORPTION 

When  dilatation  of  the  pupil  is  necessary  and  there  is  reason  to  ap- 
prehend the  results  on  the  intraocular  pressure,  homatropine  should  be 
employed,  as  its  effects  can  he  readily  controlled  by  eserine.  Numer- 
ous cases  of  poisoning  have  arisen  from  the  extensi\'e  use  of  iitropine 
in  diseased  conditions  of  the  eye.  It  is  often  asserted  that  it  passes 
down  with  the  tears  through  the  lachrymal  duct  and  is  absorbed  from 
the  nose,  throat  and  stomach,  but  as  a  matter  of  fact  it  may  be  absorbed 
from  the  conjuncti\'a  itself.  The  sjanptoms  are  generally  only  the 
milder  ones  of  atropine  poisoning — dryness  of  the  throat  and  slight 
excitement — but  dangerous  and  even  fatal  poisoning  has  also  arisen 
from  its  local  application.  In  many  cases  this  is  due  to  the  appli- 
cation of  unnecessarily  strong  solutions  to  the  eye,  but,  on  the  other 
hand,  some  patients  seem  abnormally  sensitive  to  the  action  of 
atropine,  and  hyoscine,  or  better  homatropine,  ought  to  be  preferred. 
In  rare  cases  a  curious  inflammatory  condition  of  the  conjunctiva  is  set 
up  by  atropine,  and  this  is  often  supposed  to  be  due  to  the  use  of 
irritant  preparations,  but  sometimes  seems  to  follow  the  application 
of  the  absolutely  pure  alkaloid,  and  is  apparently  an  idiosyncrasy;  it 
may,  perhaps,  be  explained  by  the  arrest  of  the  ordinary  secretions  of 
the  lachrymal  gland  and  conjunctiva  in  these  cases.  Sometimes  discs 
of  gelatin  impregnated  with  atropine  or  homatropine  sulphate  (B.  P.) 
are  applied  to  the  conjunctiva  instead  of  solutions  of  the  salts.  Eumy- 
drine  may  be  substituted  for  homatropine  in  ophthalmology,  but  offers 
no  advantages. 

To  Relax  Spasm  of  the  Intestines. — ^In  various  forms  of  colic  atropine 
is  of  very  great  service  in  lessening  pain  and  allowing  the  passage  of 
the  intestinal  contents;  for  instance,  it  is  preferable  to  morphine  in 
lead  colic,  as  it  does  not  cause  constipation.  Hernia  and  volvulus  are 
sometimes  reduced  by  atropine  injected  hypodermically  (3  mg.  or  ^V 
gr.).  It  is  often  prescribed  along  with  purgatives  in  order  to  lessen 
the  griping  which  they  produce,  and  has  been  used  as  a  laxative  in 
some  forms  of  constipation  with  considerable  success.  For  action  on 
the  bowel  it  is  generally  prescribed  in  pill  form  as  one  of  the  extracts 
of  belladonna  or  hyoscyamus.  The  object  of  prescribing  an  impure 
preparation  instead  of  the  alkaloid  is  to  allow  of  a  strong  local  action 
along  the  intestinal  wall  along  with  a  slow  and  imperfect  absorption, 
as  the  })ure  alkaloidal  salts  are  liable  to  be  absorbed  in  the  duodenum. 

To  Relax  Spasms  of  the  Involuntary  Muscles  of  Other  Organs. — In  the 
spasmodic  contraction  of  the  ureters  and  bile  ducts  due  to  calculi, 
atropine  is  occasionally  prescribed  either  in  the  form  of  a  i)ill  or  in 
solution  for  internal  use,  or  by  hypodermic  application.  In  some 
forms  of  asthma  due  to  contraction  of  the  bronchial  muscles,  atropine 
has  been  applied  locally  by  means  of  a  spray  or  given  internally,  and 
stramonium  leaves  are  often  found  of  benefit  when  made  up  into 
cigarettes  and  inhaled  when  the  attack  comes  on;'  the  smoke  has  been 

'  Another  ingredient  of  tlicse  astlinia  cig.arcttes  is  often  nitrate  of  potassium,  which 
is  reduced  to  nitrite  in  the  course  of  combustion  and  passing  into  the  kings  in  this 
form  dilates  the  Ijronchi  by  action  on  the  bronchial  mu3ch\ 


ATROPINE  333 

shown  to  contain  small  quantities  of  the  alkaloids.  Some  cases  of 
asthma  are  said  to  have  been  permanently  cured  by  treatment  with 
atropine  internally.  An  ointment  of  atropine  has  also  been  applied 
to  the  cervix  uteri  with  the  hope  of  relaxing  spasm  during  labor,  but 
the  results  are  somewhat  questionable.  Perhaps  this  action  in  relax- 
ing spasmodic  contractions  may  also  explain  the  beneficial  effects 
obtained"  in  cases  of  incontinence  of  urine  in  children,  in  which  bella- 
donna has  long  been  the  most  reliable  remedy. 

To  Lessen  Pain. — Belladonna  liniment,  plaster  and  ointment  have 
long  enjoyed  a  considerable  reputation  as  local  anodynes,  and  atropine 
has  not  infrequently  been  injected  into  painful  areas.  This  anodyne 
action  is  very  weak  compared  with  that  of  cocaine,  however,  and  the 
preparations  of  atropine  have  been  less  used  of  late  years.  In  some 
forms  of  gastralgia  atropine  has  also  been  suggested. 

The  Effects  on  the  Central  Nervous  System  of  the  members  of  this 
group  are  very  different,  and  the  purposes  for  which  they  are  used^  are 
diametrically  opposed.  Atropine  is  used  as  a  stimulant  in  various 
conditions  of  depression  of  the  brain  and  medulla  oblongata.  Thus, 
in  collapse  its  hypodermic  injection  may  be  of  use  to  stimulate  the 
respiration  and  at  the  same  time  to  free  the  heart  from  excessive  in- 
hibition. In  dangerous  poisoning  from  narcotic  and  hypnotic  drugs, 
more  especially  in  opium  poisoning,  atropine  has  been  largely  used.  A 
long  and  weary  dispute  as  to  the  value  of  atropine  in  those  cases  has 
been  carried  on,  for  the  history  of  which  the  reader  is  referred  to  the 
recent  paper  by  Bashford.  The  results  indicate  that  atropine  is  useful 
in  morphine  poisoning  through  stimulating  the  respiratory  centre,  which 
is  the  danger  point.  But  it  must  be  employed  in  small  qunatities 
(1.5  mg.  or  4V  gr-)j  as  large  doses,  such  as  have  frequently  been  advised, 
tend  to  depress  the  central  nervous  system  and  thus  to  aid  rather  than 
to  antagonize  the  action  of  morphine  on  the  respiration.  It  may  be 
questioned  whether  in  any  case  atropine  may  not  be  replaced  by  caffeine 
with  advantage.  The  former  stimulates  the  medullary  centres,  but 
subsequently  paralyzes  them,  while  caffeine,  even  in  comparatively 
large  quantities,  does  not  seem  to  have  a  depressant  action  in  man. 

Atropine  at  one  time  had  some  reputation  in  the  treatment  of  epi- 
lepsy. It  has  been  shown  both  clinically  and  experimentally  that  this 
reputation  was  undeserved,  the  number  of  attacks  and  their  violence 
being  rather  increased  than  diminished  by  its  exhibition;  the  belief 
in  its  powers  arose  from  the  use  of  impure  preparations  containing 
hyoscine. 

In  some  spasmodic  diseases,  such  as  whooping-cough,  belladonna 
preparations  have  long  enjoyed  a  wide  reputation;  this  may  possibly 
be  explained  either  by  the  hyoscine  reducing  the  excitability  of  the 
respiratory  centre,  or  by  atropine  relaxing  bronchial  spasm. 

Hyoscine,  or  scopolamine,  has  been  used  as  a  narcotic  to  depress  the 
central  nervous  system;  it  is  of  great  efficacy  in  insanity,  producing 
sound  and  refreshing  sleep,  but  is  of  less  value  in  controlling  the 
excitement  during  the  day,  and  may  in  fact  increase  it.      Hyoscine  is 


334  SUBSTANCES  ACTING  AFTER  ABSORPTION 

also  used  with  benefit  in  various  forms  of  tremor  of  central  origin, 
and  is  said  to  lessen  sexual  excitement.  Its  In-pnotio  action  does  not 
seem  to  be  of  the  same  nature  as  that  of  opium,  for  in  sleeplessness 
produced  by  pain  it  is  of  comparatively  little  value,  and  it  has  no 
power  to  relieve  pain  itself.  It  differs  from  chloral  in  not  inducing 
deep  sleep,  for  i)atients  under  the  influence  of  hyoscine  can  always  be 
aroused  and  are  much  less  confused  than  after  chloral.  The  special 
indications  for  hyoscine  seem  to  be  sleeplessness  due  to  abnormal 
activity  of  the  motor  areas  and  some  forms  of  tremor. 

Comparatively  recently  morphine  and  hyoscine  have  been  injected 
as  a  preliminary  to  surgical  operations,  but  as  a  general  rule  the 
narcosis  induced  is  insufficient.  As  a  preliminary  to  the  use  of  ether 
the  procedure  seems  to  be  of  value,  as  much  less  of  the  anaesthetic  is 
required;  10  mgs.  (|  gr.)  of  morphine  and  0.3  mg.  {j^^j  gr.)  of  hyo- 
scine are  injected  1|  hours  before  the  operation. 

Poisoning. — In  cases  of  poisoning  with  belladonna  and  its  allies  the 
treatment  is  purely  symptomatic.  In  the  excitement  stage  sedatives 
may  be  used;  perhaps  chloroform  and  ether  are  best,  as  their  effects 
are  more  transient  than  the  others.  Morphine  has  been  advised,  but 
its  action  on  the  respiratory  centre  renders  its  use  dangerous,  as  in 
severe  atropine  poisoning  the  stimulation  soon  passes  into  depression, 
and  the  effects  of  the  poison  and  its  so-called  antidote  therefore  sup- 
plement each  other.  Chloroform  and  ether,  on  the  other  hand,  may 
be  used  to  control  the  spasms  and  then  stopped  when  these  pass  off. 
In  the  depression  stage  cafTeine  may  be  used,  and  eventually  artificial 
respiration.  Pilocarpine  is  of  course  useless,  as  it  does  not  antagonize 
atropine  in  the  brain,  which  is  the  point  of  danger. 

Bibliography. 

Bezold  u.  Bloebaum.     Untersuch.  a.  d.  phj'siol.  Laborator.  zu  Wiirzhurg,  i,  p.  1. 

Heidenhain.     Pfliiger's  Archiv,  v,  p.  309,  and  ix,  p.  3.35. 

Luchsinger.     Ibid.,  xv,  p.  482;    xviii,  p.  587,  and  xxvi,  p.  459. 

Albertoni.     Arch.  f.  exp.  Path.  u.  Pharm.,  xv,  p.  258. 

Hammerhacher.     Pfliiger's  Arch.,  xxxiii,  p.  228. 

Mironow.     Arch,  de  Science  biologique,  iii,  p.  353. 

On.     Therap.  Gaz.,  1887,  p.  511. 

Alms.     Arch.  f.  Anat.  u.  Phys.,  1888,  p.  416. 

Bayliss  and  Starling.     Journ.  of  Physiol.,  xxiv,  p.  99. 

Dixon.     Ibid.,  xxviii,  p.  57. 

Magnus.     Ergebnisse  der  Physiol.,  ii  (2),  p.  653. 

Riegel.     Ztschr.  f.  klin.  Med.,  xxxvii,  p.  381. 

Schiff.     Arch.  f.  Verdauungskrankh.,  vi,  p.  107. 

Gottlieb.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxvii,  p.  218. 

Cushny.     Journ.  of  Physiology,  xxx,  p.  176,  xxxii,  p.  .Wl. 

Bashford.     Arch,  internat.  de  Pharmacodyn.,  viii,  p.  311. 

Miiller.     Diss.,  Dorpat,  1891. 

Melzner.     Arch.  f.  exp.  Path.  u.  Pharm.,  Ixviii,  p.  110. 

Mathews.     Am.  .lourn.  of  Physiol.,  iv,  p.  482. 

Schiller.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxviii,  p.  71. 

^Inrep.     Pfliigc'r's  Archiv,  xxi,  p.  78. 

Schullz.     Arch.  f.  Anat.  u.  Phys.,  1898,  p.  53. 

Strieker  u.  Spina.     Wiener  Sitziiiigsbcr.,  Math.-nat.  Classe,  Ixxx,  Al)i.  iii.  p    117. 

Spiro.     Arch.  f.  oxp.  Path.  u.  Pharm.,  xxxviii,  p.  113. 

Wiechowski.      Ibid.,  xlvi,  p.  154. 

Compare  also  the  Literature  of  pilocarpine  and  nmscarine,  nicotine,  and  physostigmine. 


AGARIC  IN  335 


Agaricin. 


White  Agaric  (Agaricus  albus,  Boletus  Laricis),  a  fungus  growing 
on  the  European  larch  tree,  was  formerly  a  purgati\-e  and  antihydrotic 
of  some  repute.  Its  use  to  lessen  the  perspiration  (antihydrotic)  has 
been  revived  of  late  years,  or  rather  a  preparation  known  as  agaricin 
and  containing  the  active  principle  has  been  introduced  into  thera- 
peutics. Agaric  acid,  the  active  constituent,  belongs  to  the  malic  acid 
series  and  has  the  formula  Ci4H27(OH)(COOH)2. 

Action.— Both  the  acid  and  its  sodium  salt  irritate  the  mucous  membranes 
and  wounded  surfaces,  and  cause  inflammation  and  even  suppuration  when 
injected  subcutaneously.  Large  quantities  irritate  the  stomach  and  intestine 
and  cause  ^'omiting  and  purging,  but  these  are  more  hable  to  arise  from  the 
impure  agaricin  owing  to  its  containing  resinous  acids.  Injected  into  the 
frog,  agaric  acid  paralyzes  the  central  nervous  system,  weakens  the  heart, 
and  stops  the  secretion  of  the  skin  glands.  In  mammals  the  intravenous  in- 
jection of  agaric  acid  is  followed  by  depression,  weakness,  dyspnoea,  and  death. 
The  medulla  oblongata  is  first  stimulated  and  then  paralyzed,  as  is  shown  by 
the  blood-pressure  first  rising  and  then  falling  to  zero,  while  the  heart  is  primarily 
slowed  by  inhil^itory  action  and  later  regains  its  rhythm,  eventually  to  fail 
after  the  arrest  of  the  breathing.  Animals  can  only  be  poisoned  with  difficulty  by 
the  subcutaneous  injection  of  agaricin,  and  no  general  symptoms  are  elicited 
when  it  is  administered  by  the  mouth. 

The  most  interesting  feature  of  the  action  of  agaric  salts  is  the 
arrest  of  the  sweat  secretion,  which  is  caused  by  peripheral  action,  for 
stimulation  of  the  nerves  of  the  cat's  foot  fails  to  elicit  perspiration 
after  its  ingestion.  It  thus  acts  on  the  same  peripheral  mechanism 
as  atropine  in  all  probability,  that  is,  on  the  terminations  of  the  secre- 
tory nerves,  but  differs  from  atropine  in  acting  only  in  the  sweat 
glands,  for  the  saliva,  tears  and  other  secretions  are  not  hindered  by 
it,  and  may,  in  fact,  be  increased  by  its  causing  nausea.  It  is  also 
devoid  of  action  on  the  nerve  terminations  in  the  heart  and  pupil. 
Atropine  acts  much  more  powerfully  than  agaric  acid,  at  least  twenty 
times  as  much  of  the  latter  being  required  to  arrest  the  sweat 
secretion. 

Uses. — Agaricin  is  used  in  the  night  sweats  of  phthisis  and  other 
similar  conditions  and  is  generally  given  in  pill  form  in  doses  of  5-60 
mgs.  (tV~1  gr.).  The  commercial  agaricin  often  contains  a  large  per- 
centage of  impurities  and  has  to  be  given  in  larger  quantities,  but  the 
treatment  ought  to  be  begun  with  small  doses.  Tolerance  is  said  to  be 
acquired  after  some  time,  and  the  dose  has  then  to  be  increased.  The 
best  results  are  got  when  the  pills  are  taken  5-6  hours  before  retiring, 
as  the  acid  is  only  slowly  absorbed.  If  agaricin  causes  intestinal 
irritation  and  diarrhoea,  it  may  be  given  with  opium,  but  as  in  phthisis 
all  irritation  of  the  bowel  is  to  be  avoided,  the  remedy  ought  perhaps 
to  be  stopped  when  any  such  disturbance  arises.  Camphoric  acid,  which 
was  formerly  advised  to  lessen  the  secretion  of  sweat  in  phthisis;  appears 
to  have  little  or  no  effect  and  should  be  discarded  (Vejux-Tyrode). 


336  SUBSTANCES  ACTING  AFTER  ABSORPTION 


Bibliography. 

Hofmeisler.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxv,  p.  189. 
Vejux-Tyrode.     Arch,  internat.  de  Pharmacodyn.,  xviii,  p.  393. 


Xn.     PILOCARPINE  AND  MUSCARINE. 

Pilocarpine  and  muscarine,  two  altcaloids  of  very  different  chemical 
constitution,  possess  similar  properties  from  a  pharmacological  point 
of  view.  Pilocarpine  (CUH16N2O2)  is  found  along  with  Isopilocarpine 
in  the  leaves  of  several  species  of  Pilocarpus.^  Muscarine,  the  alkaloid 
of  one  of  the  poisonous  mushrooms,^  Agaricus  muscarius,  or  Amanita 
muscaria,  is  very  closely  related  chemically  to  choline,  which  is  a  con- 
stituent of  animal  tissues. 

The  probable  formula?  of  pilocarpine  and  muscarine  are 

C2H6— CH CH— CH2— C— N  (CH3)\  CH— (0H)2 

I              I                     II  >CH  I 

CO         CH2  CH N-^'  CHz— N(CH3)30H 

\    / 

O  ,      ■ 

Pilocarpine.  ^,''0'      '  Muscarine. 

Choline  (HO — N(CH3)3CH2CH20H)  resembles  muscarine  in  its  action, 
and  some  of  its  compounds  are  so  similar  to  muscarine  that  choline- 
nitrite  ether  was  formerly  known  as  synthetic  muscarine.  Some  other 
trimethylammonium  bases  also  present  resemblances  to  muscarine,  but 
none  of  them  is  so  poisonous,  and,  like  the  choline  derivatives,  they  all 
differ  from  muscarine  in  inducing  a  curara-like  paralysis  in  the  frog 
(Dale). 

Arecoline  (C8H13NO2),  one  of  the  alkaloids  contained  in  Betel  Nut 
(Areca  catechu),  resembles  pilocarpine  in  its  action  but  is  more  powerful. 

Pilocarpine  and  muscarine  act  on  the  same  peripheral  organs  and 
apparently  on  the  same  receptive  substances  as  atropine,  but  they 
arouse  these  receptors  to  activity,  while  atropine  depresses  them.  The 
receptors  may  lie  on  the  path  of  impulses  from  the  nerves  to  the  con- 
tractile or  secretory  substance,  and  the  effect  of  pilocarpine  and  mus- 
carine is  then  identical  with  that  of  nerve  stimulation  (p.  341). 

Symptoms. — The  symptoms  of  poisoning  in  man  commence  with  a 
v"cry  marked  secretion  of  saliva,  followed  soon  after  by  excessive  i)er- 
spiration  and  a  flow  of  tears.  After  muscarine  and  sometimes  after 
pilocarpine,  nausea,  retching  and  vomiting,  pain  in  the  abdomen  and 
violent  movement  of  the  intestines  causing  profuse  watery  evacuations, 
are  next  observed.  The  pulse  is  sometimes  quickened,  sometimes  very 
slow  and  irregular;  the  pupil  is  contracted,  and  the  sight  is  accommo- 

'  Pilocarpidine  has  been  isolated  from  the  leaves  of  Pilocarpus  Jaborandi  only,  and  is 
practically  inirt.  Jaborine  was  formerly  stated  to  occur  with  pilocarpine  and  to  possess 
an  action  resembling  that  of  atropine,  but  more  recent  investigators  have  failed  to  con- 
firm either  of  these  statements. 

-  Muscarine  is  accompanied  in  thc^  .Amanita  by  another  poison  which  differs  from  it  in 
inducing  convulsions  and  other  symptoms  of  central  nervous  stimulation  (Harmsen). 


PILOCARPINE  AND  MUSCARINE 


337 


dated  for  near  objects.  The  respiration  is  often  quick  and  dyspnoeic, 
and  rales  may  he  heard  over  the  bronchi,  denoting  an  accumuUition  of 
mucus  in  them.  Giddiness  and  confusion  of  ideas  are  complained  of, 
and  after  pilocarpine  tremors  and  feeble  convulsive  movements  are 
sometimes  observed,  but  the  nervous  symptoms  are  not  so  conspicuous 
as  those  from  the  peripheral  organs.  Eventually  the  respiration 
becomes  slower  and  great  weakness  in  the  movements  manifests  itself, 
but  the  consciousness  remains  more  or  less  perfect  till  the  breathing 
ceases. 

Action. — The  salivary  and  lachrymal  Glands,  the  mucous  glands  of 
the  mouth,  throat,  nose  and  deeper  respiratory  passages,  the  gastric 
secretory  glands,  the  pancreas,  and  probably  the  intestinal  glands,  all 
secrete  copiously  after  muscarine  and  pilocarpine.  The  sweat  glands 
and  the  ceruminous  glands  of  the  ears  are  likewise  roused  to  unwonted 


Fig.  31 


5  10    20   30   40   50   tjO   70   80   90   100   110  130 

Chart  of  the  gastric  secretion  in  the  dog  under  pilocarpine  and  atropine.  Three 
observations  were  made:  in  one  milk  alone  was  given,  in  another  milk  with  pilocarpine, 
and  in  a  third  milk  with  atropine.  The  amount  of  secretion  was  noted  in  a  small  isolated 
pouch  of  the  stomach,. and  is  indicated  graphically  in  the  chart.     (Riegel.) 

activity,  and  many  other  glandular  structures  are  also  stimulated. ' 
There  is  evidence  that  the  suprarenal  glands  respond  to  pilocarpine 
with  an  increased  secretion  of  adrenaline  into  the  blood,  and  this  explains 
some  anomalous  reactions  met  with  under  pilocarpine. 

In  most  cases  the  solids  of  the  secretions  are  increased  as  well  as 
the  fluids,  although  to  a  somewhat  less  extent.  The  bile,  the  urine 
and  the  milk  do  not  seem  to  be  affected  directly  by  pilocarpine  and 
muscarine,  although  they  may  be  reduced  in  amount  or  otherwise 
modified  by  the  withdrawal  of  large  quantities  of  fluid  from  the  body 
by  other  channels. 

After  a  small  quantity  of  atropine,  pilocarpine  and  muscarine  in 
ordinary  quantities  produce  no  increase  in  any  of  the  secretions.  This 
indicates  that  the  seat  of  action  of  these  poisons  is  not  the  secretory 


1  A  curious  example  of  this  has  been  shown  by  Dreser  to  occur  in  the  fish,  in  which  the 
swimming  bladder  secretes  more  oxygen  than  usual. 
22 


33S  SUBSTANCES  ACTING  AFTER  ABSORPTION 

cells,  for  it  has  been  shown  that  atropine  paralyzes  only  the  niyonenral 
junctions  and  leaves  the  cells  uninjured.  On  the  other  hand,  section 
of  the  secretory  nerves  does  not  alter  materially  the  action  of  pilocarpine 
or  muscarine,  for  the  secretion  of  perspiration  in  the  foot  of  the  cat 
is  increased  by  pilocarpine  even  after  section  of  the  sciatic  nerve.* 
The  seat  of  action  of  pilocarpine  and  muscarine  is  therefore  the  myo- 
neural connections  between  the  nerves  and  the  epithelial  cells.  These 
are  stimulated  by  the  members  of  this  group  and  paralyzed  by  atropine, 
and  these  two  series  therefore  form  antidotes  to  one  another. 

The  salivary  secretion  may  amount  to  half  a  litre  or  more  in  the 
course  of  2-3  hours  after  an  injection  of  pilocarpine,  while  the  skin 
and  lungs  excrete  even  a  larger  quantity  of  fluid  in  the  same  time. 
The  weight  is  thus  considerably  reduced  by  pilocarpine  owing  to  the 
loss  of  fluid,  which  may,  according  to  some  authors,  amount  to  2-4 
kilogrammes  (4^-9  lbs.)  after  a  single  dose. 

The  secretion  of  the  milk  is  not  increased  by  pilocarpine.  The  sugar 
of  the  blood  has  been  found  increased  by  pilocarpine,  and  this  has 
been  attributed  to  its  acting  on  the  terminations  of  the  nerves  in  the 
li^•er  which  regulate  the  glycogenic  functions  of  that  organ. 

The  increased  activity  of  the  glands  is  accompanied  by  an  accelera- 
tion of  the  blood  current  through  them,  but  this  is  a  result  of  their 
stinnilation  from  any  cause  whatever,  and  is  probably  not  due  to  the 
direct  action  of  the  alkaloids  on  the  vessels.  The  redness  of  the  skin, 
especially  of  the  face,  so  often  observed  after  pilocarpine,  may  perhaps 
be  explained  in  this  way,  as  an  accompaniment  of  the  augmented 
activity  of  the  sweat  glands. 

Muscle. — Nausea  and  discomfort  in  the  stomach,  followed  by  retch- 
ing and  vomiting,  are  rarely  seen  after  pilocarpine,  but  form  some  of 
the  earliest  symptoms  of  muscarine  poisoning.  They  are  not  pro- 
duced by  the  saliva  swallowed,  as  was  formerly  supposed,  but  by  the 
action  of  the  alkaloids  on  the  stomach,  and  as  these  symptoms  are 
removed  by  atropine  in  small  quantities,  it  is  inferred  that  pilocar- 
pine and  muscarine  act  on  the  same  receptors  as  atropine,  but  in  the 
opposite  sense,  stimulating  instead  of  paralyzing  them.  These  recep- 
tors do  not  appear  to  lie  in  the  path  of  nerve  impulses  in  the  stomach, 
as  is  shown  by  the  gastric  muscle  still  responding  to  stimulation  of 
the  vagus  after  the  receptors  are  paralyzed  by  atropine. 

The  intestines  are  also  set  in  umisually  active  movement  by  a  sim- 
ilar j)rocess,  and  repeated  evacuation  of  their  contents  follow.  These 
are  at  first  of  firm  consistency,  but  later,  as  the  continued  peristalsis 
carries  down  the  contents  of  the  small  intestine,  which  have  not  lain 
long  enough  in  the  bowel  to  allow  of  the  absorption  of  their  fluid,  the 
fjcces  contain  more  water  than  usual.  This  fluidity  of  the  stools  may 
also  be  due  in  part  to  an  augmentation  of  the  intestinal  secretion,  but 
this  has  not  been  satisfactorily  demonstrated.     Even  after  the  bowel 

'  In  man  it.  is  found  that  after  division  of  a  nerve  pilocarpine  no  lonser  causes  perspira- 
tion in  the  iiinti.  And  in  cases  of  coniijlete  interruption  of  the  nervous  paths  in  the 
cord,  pilocarpine  causes  no  sweating  in  the  lower  part  of  the  body. 


PILOCARPINE  AND  MUSCARINE  339 

has  been  (completely  evacuated,  the  persistent  peristalsis  betrays  itself 
in  painful  straining.    (See  Fig.  29,  p.  322.) 

The  muscle  of  a  number  of  other  organs  contracts  after  pilocarpine 
or  muscarine  from  stimulation  of  receptors  similar  to  those  in  the 
stomach  and  bowel.  Thus  the  sj)Icen,  bladder  and  pregnant  uterus 
are  contracted,  and  in  the  case  of  the  bladder  repeated  evacuation  and 
straining  may  occur.  In  some  animals  the  uterus  is  inhibited  by 
pilocarpine  and  muscarine,  this  being  the  usual  action  in  the  non- 
pregnant cat. 

In  some  other  forms  of  muscle,  pilocarpine  and  muscarine  cause 
contraction  by  acting  on  receptors  which  lie  on  the  path  of  the  nerve 
impulses.  Thus  in  poisoning  with  these  and  also  on  local  applica- 
tion, the  pupil  becomes  extremely  narrowed,  and  at  the  same  time  the 
ciliary  muscle  contracts  so  that  the  lens  is  accommodated  for  short 
distances.  Both  of  these  phenomena  are  due  to  stimulation  of  the 
myoneural  junctions  in  the  intraocular  muscles  (Fig.  26,  p.  320),  for 
atropine  removes  the  contraction  and  at  the  same  time  interrupts  the 
passage  of  impulses  from  the  nerve  to  the  muscle.  This  does  not 
seem  to  be  due  to  action  on  the  anatomical  ends  of  the  nerves,  for 
pilocarpine  continues  to  act  after  these  have  degenerated.  The  point 
of  action  is  therefore  probably  a  receptor  interpolated  between  the 
actual  end  of  the  nerve  fibre  and  the  contractile  substance  of  the 
muscle;  that  the  contractile  substance  is  not  affected  is  shown  by  its 
continuing  to  contract  after  atropine  has  paralyzed  the  pilocarpine 
receptor. 

The  intraocular  pressure  is  reduced  by  muscarine  and  pilocarpine, 
although  they  may  increase  it  at  first.  This  is  due  to  the  iris  being 
drawn  up  by  its  contraction  and  thus  allowing  free  egress  to  the  intra- 
ocular fluids  (see  Atropine,  p.  322).  The  bronchial  muscles  are  con- 
tracted by  pilocarpine  and  muscarine,  which  here  also  appear  to  act  on 
myoneural  receptors  at  the  terminations  of  the  pneumogastric  nerves. 

All  these  muscular  phenomena  are  prevented  by  the  previous  ad- 
ministration of  atropine.  This  antagonistic  action  has  been  carefully 
studied  in  the  eye,  where  it  is  found  that  after  pilocarpine  has  pro- 
duced contraction  of  the  pupil,  the  administration  of  very  small  quan- 
tities of  atropine  is  followed  by  dilatation.  Strong  pilocarpine  solution 
again  dropped  into  the  eye  will  again  reduce  the  size  of  the  pupil,  but 
the  quantity  required  is  vastly  more  than  in  the  normal  eye,  and  this 
second  contraction  may  again  be  removed  by  comparatively  small 
quantities  of  atropine.  In  the  bird's  pupil,  in  which  the  muscle  is 
striated,  muscarine  and  pilocarpine  have  no  effect,  the  terminations 
of  the  nerves  being  evidently  different  from  those  in  mammals. 

The  action  of  pilocarpine  and  muscarine  on  the  Circulation  presents 
some  differences  in  different  species  of  animals.  On  the  application 
of  either  to  the  frog's  heart,  its  rhythm  is  at  once  slowed,  the  diastolic 
pause  being  much  increased  in  length  and  the  contractions  lessened  in 
force.  Soon  the  heart  ceases  to  beat  entirely,  although  irritation  of 
its  muscle  by  mechanical  or  chemical  means  elicits  one  or  more  con- 


340      .  SUBSTANCES  ACTING  AFTER  ABSORPTION 

tractions.  Tlie  symptoms  produced  are  exactly  those  seen  on  stimula- 
tion of  the  vagus  by  electrical  shocks,  and  muscarine  has  long  been 
believed  to  act  by  stimulation  of  the  inhibitory  mechanism  in  the 
heart.  The  point  of  action  is  not  the  ganglia  on  the  inhibitory  fibres 
for  muscarine  is  effective  after  these  are  completely  paralyzed  by 
nicotine,  and  it  also  acts  on  the  apex  of  the  frog's  ventricle,  in  which 
no  ganglia  whatever  have  been  found.  The  action  must  therefore  be 
localized  at  some  ])oint  between  the  ganglia  and  the  actual  contractile 
substance,  for  the  latter  maintains  its  normal  character  responding 
with  a  contraction  to  stimuli.  Muscarine  is  therefore  generally  held  to 
stimulate  the  myoneural  junctions  between  the  inhil)itory  fibres  and  the 
contractile  substance  of  the  muscle.  Atropine  removes  this  standstill 
by  paralyzing  the  junctions,  but  larger  quantities  of  muscarine  or 
pilocarpine  will  again  overcome  the  atropine  action  and  restore  the  stand- 
still or,  at  any  rate,  the  slow  pulse.  Digitalin  and  its  allies  remove  the 
standstill  by  increasing  the  irritability  of  the  muscle  until  the  inhibition 
can  no  longer  hold  the  heart  in  check,  but  throughout  the  rhythm  caused 
by  these  the  activity  of  the  vagus  can  be  seen  in  the  slowness  of  the 
beat  and  the  prolongation  of  the  diastole.  When  the  heart  is  slowed 
by  muscarine,  stimulation  of  the  vagus  is  more  effective  than  normally, 
the  action  of  the  drug  being  added  to  that  of  the  electrical  stimulus. 

In  rabbits  and  cats  similar  changes  are  seen  in  the  circulation  after 
muscarine.  The  heart  is  slowed  or  brought  to  a  complete  standstill, 
the  blood  pressure  falls,  and  all  the  symptoms  produced  by  anjiemia 
of  the  brain  may  follow,  but  the  animal  becomes  again  perfectly  normal 
on  the  administration  of  small  quantities  of  atropine.  Pilocarpine 
differs  from  muscarine  here  in  several  particulars,  for  it  soon  depresses 
the  inhibitory  fibres  and  the  heart  regains  its  former  rhythm,  but  the 
cardiac  muscle  is  then  affected,  so  that  the  contractions  rapidly  become 
weaker  and  slower  again,  and  this  secondary  slowing  is  not  remo\'ed  l)y 
atropine;  the  vasomotor  centre  also  becomes  gradually  weakened  by 
large  doses,  so  that  the  bloodvessels  remain  somewhat  dilated,  and  the 
arterial  tension  remains  low  even  after  atropine. 

In  dogs  the  stimulation  of  the  inhibitory  fibres  seems  sometimes  to 
be  entirely  absent  after  pilocarpine  and  muscarine,  and  in  man  this  is 
very  frequently  the  case.  Instead  of  a  slow  pulse  and  lessened  tension 
of  the  arteries,  acceleration  and  increased  blood-pressure  are  then 
observed.  This  is  accompanied  in  man  by  marked  pal])itation  and 
discomfort  in  the  region  of  the  heart  and  by  dilatation  of  the  skin 
vessels,  esi)ecially  of  those  of  the  face.  In  other  cases,  howexer,  the 
same  circulatory  disturbances  are  produced  as  in  the  cat  and  rabbit 
(Fig.  32).  The  acceleration  of  the  heart  and  palpitation  may  perhaps 
arise  from  the  nausea,  which  may  be  sufficient  to  overcome  the  inhibitory 
stimulation. 

In  embryo  hearts  nniscarinc,  in  ordinary  (luaiititics,  i)roduccs  no 
change  whatever  during  the  hrst  b")()  hours  of  life  (in  the  chick).  The 
explanation  of  this  phenomenon  is  that  the  inhibitory  ncrxes  ha\c  not 
been  de\elopetl  at  this  stage,  and  after  their  (k'W'lojjment  is  complete, 


PILOCARPINE  AND  MUSCARINE 


341 


muscarine  acts  on  the  heart  as  in  the  aihilt.  The  a])sence  of  slowing;  in 
some  of  the  invertehrates  may  be  (hie  to  a  simihir  cause,  although 
this  does  not  hold  good  for  the  crab,  in  which  there  is  a  well-defined 
inhibitory  apparatus  but  in  which  muscarine  causes  acceleration. 


Fig.  32 


LLULLl 


B      A 


Tracings  of  the  movement  of  the  auricle  (upper)  and  ventricle  (lower)  of  the  dog 
under  muscarine.  During  contraction  the  levers  move  upwards;  during  relaxation  down- 
wards. A-B,  normal.  At  B,  muscarine  was  injected  intravenously  and  at  C  it  began  to 
act.  The  movements  of  the  ventricles  are  slower  and  a  distinct  pause  is  seen  in  diastole. 
The  contraction  is  less  complete,  while  the  heart  relaxes  more  than  usual  during  diastole. 
The  auricle  soon  comes  to  a  standstill  in  diastole.  Compare  the  effects  of  stimulation 
of  the  vagus  in  the  first  part  of  Fig.  30,  page  324. 


Peripheral  Action.^Muscarine  and  its  allies  have  generally  been  regarded 
as  acting  ou  the  terminations  of  a  series  of  autonomic  nerves,  chiefly  belonging 
to  the  craniosacral  division,  but,  on  the  other  hand,  some  observers  have  held 
that  the  action  is  a  direct  one  on  the  organs  themselves  and  that  the  nerves 
are  not  involved.  The  arguments  in  favor  of  the  action  on  the  nerve  ends 
have  been  the  exact  similarity  in  the  effects  of  vagus  stimulation  and  of  mus- 
carine in  the  heart  and  the  fact  that  drugs,  such  as  atropine,  which  paralyze 
the  nerves,  also  antagonize  muscarine.  The  second  argument  is  weakened 
by  the  observation  that  the  muscarine  action  on  such  organs  as  the  intestine 
and  uterus  can  be  abolished  by  atropine  though  it  has  no  effect  on  the  results 
of  nerve  stimulation,  so  that  the .  seat  of  action  of  muscarine  and  atropine 
cannot  lie  on  the  path  of  the  nerve  impulses  in  these  organs.  The  similarity 
in  the  action  of  muscarine  and  of  nervous  stimulation  is  so  great,  however, 
that  the  receptive  substance  for  the  alkaloid  must  be  closely  connected  with 
the  nerve  path  and  must  undergo  the  same  seasonal  and  other  changes  as  the 
myoneural  connections.  It  is  possible,  however,  that  both  muscarine  and 
nerve  stimulation  may  affect  the  same  process  and  that  the  parallelism  in 
their  effects  may  be  explained  in  this  way;  for  example,  if  a  change  in  the 
permeability  of  the  membranes  of  a  cell  is  the  essential  feature  of  nerve 
action,  muscarine  may  also  have  this  result  while  atropine  may  oppose  this 
muscarine  action.  In  the  case  of  the  salivary  gland  cells,  atropine  opposes 
not  only  the  action  of  muscarine  in  increasing  the  permeability  but  also  that 
of  the  nerve  impulse,  while  in  the  intestine  atropine  neutralizes  the  action  of 
muscarine  but  not  that  of  the  nerve  impulse:  in  each  case  the  drugs  act  on 


342  SUBSTANCES  ACTJNC  AFTER  ABSORPTION 

sonic  structure  difTeront  from  the  actual  motor  or  secretory  sul)stance  and  also 
(lilTcrent  from  tlic  anatomical  nerve  ends. 

According  to  Straub,  muscarine  acts  on  the  heart  only  as  it  penetrates  into 
the  jnusclc  cells,  and  once  arrived  in  the  interior  has  no  further  action.  If 
dilute  solutions  are  apjjlied  to  the  heart,  the  tdkaloid  may  slowly  accumulat(; 
in  the  muscle  without  the  heart  being  arrested.  If  now  the  muscarine  be  e.x- 
tracted  from  the  muscle  and  applied  to  another  heart  in  concentrated  solution, 
this  second  heart  is  immediately  arrested.  The  action  therefore  depends  on 
the  concentration  hi  which  the  drug  is  applied  and  not  on  the  amount  in  the 
muscle;  in  other  words,  the  action  is  exerted  in  the  process  of  absorjjtion  and 
not  after  absorption.  Straub  holds  that  atropine  opjioses  mus(;arine  by  retarding 
its  permeation  into  the  cell  and  thus  producing  the  same  result  as  if  the  con- 
centration of  the  muscarine  solution  were  lessened.  On  adding  more  muscarine 
so  as  to  render  the  solution  very  concentrated  the  permeation  is  accelerated 
in  spite  of  the  atrojjine  and  the  muscarine  action  reappears. 

The  Respiratory  centre  is  not  acted  on  directly  liy  small  quantities 
of  pilocarpine  and  muscarine.  But  the  changes  in  the  circulation 
lessen  the  amount  of  blood  passing  through  the  lungs,  and  the  contrac- 
tion of  the  bronchial  muscle  may  seriously  retard  the  movement  of 
the  air  and  thus  impair  the  aeration  of  the  blood.  The  oedema  of  the 
lungs  which  is  often  observed  in  cats  and  rabbits  poisoned  with  the 
members  of  this  series,  and  which  has  also  occurred  in  fatal  poisoning 
in  man,  arises  from  the  slowing  of  the  circulation  through  the  lungs 
from  the  cardiac  action.  Large  quantities  of  pilocarpine  cause  a 
tendency  to  convulsive  movements  and  a  more  rapid  and  labored 
respiration.  Eventually  the  respiration  becomes  slow  and  weak  and 
asphyxia  follows. 

It  has  been  found  that  pilocarpine  increases  the  Leucocytes  of  the 
blood  from  its  acting  on  the  spleen  and  other  leucocyte-forming  tis- 
sues; it  is  possible  that  the  leucocytes  are  pressed  out  of  the  spleen 
by  the  contractions  of  the  smooth  muscle.  Both  polymorphonuclear 
and  mononuclear  cells  are  increased  in  the  blood.  liuzicka  states 
that  the  Malpighian  corpuscles  of  the  spleen  are  increased  in  number 
after  pilocarpine. 

The  Temperature  is  said  to  be  increased  by  pilocarpine,  although 
only  to  a  very  small  extent,  and  the  carbonic  acid  excretion  is  increased 
through  the  drug  increasing  the  acti\it\'  of  the  glands  and  other  organs. 
After  the  perspiration  is  fully  developed  the  internal  temperature  is 
generally  reduced,  especially  in  fever. 

Some  symptoms  occur  in  cases  of  j)ois()ning  which  point  to  .some 
action  of  the  alkaloids  on  the  Central  Nervous  System,  Thus  frogs 
develop  well-marked  convulsions,  and  even  in  the  higher  animals  and 
man  tremor  and  slight  convulsive  movements,  such  as  hiccough,  lia\'e 
been  observed.  The  collapse  which  is  seen  in  the  later  stages  may  be 
central  in  origin  but  probably  is  largely  the  result  of  the  perii)hcral 
action,  and  the  convulsions,  which  occur  in  some  cases,  arise  from  ana'inia 
of  the  brain  as  the  result  of  the  cardiac  weakness. 

Pilocari)ine  and  muscarine,  while  resembling  each  other  in  general, 
present  some  points  of  diiVerence,  which  are  of  the  greatest  ini))ortance 
as  regards  their  use  in  thera])eutics.     Muscarine  has  ])ractica]ly  never 


PILOCARPINE  AND  MUSCARINE  ?A^ 

been  introchiced  into  medical  prac-tioo,  because,  while  its  action  on  the 
secretions  is  quite  equal  to  that  of  pilocarpine,  the  gastric  symptoms 
are  produced  much  more  readily  by  it.  It  is  also  a  much  more  powerful 
poison  than  i)ilocari)ine,  and  is  less  easily  prej)ared  in  pure  form. 

PiLocARPiN.E  Hydrochloridum  (U.  8.  P.)  (C11H16N2O2HCI),  the  hydro- 
chloride of  an  alkaloid  obtained  from  the  leaves  of  Pilocarpus  Jaborandi  or 
inicrophyllus,  forms  small,  white  crystals,  odorless,  with  a  slight  bitter  taste, 
deliquescent  in  the  air,  very  soluble  in  water  and  alcohol.    0.010  G.  (i  gr.). 

PiLocARPiN.E  NiTRAS  (U.  S.  P.,  B.  P.)  (Ci,H,6N.,O.HN03),  the  nitrate  of 
an  alkaloid  obtained  from  Pilocarpus  leaves,  forms  a  white  crystalline  powder, 
which  is  soluble  in  8-9  parts  of  cold  water,  and  is  freely  soluble  in  hot  alcohol. 
0.01  G.  (!  gr.);  B.  P.,  ^-^  gr. 

Therapeutic  Uses  of  Pilocarpine,^ — Its  action  on  the  sweat  glands  renders 
pilocarpine  much  the  most  powerful  sudorific  in  the  pharmacopoeia, 
and  it  is  used  internally  almost  exclusively  for  this  purpose.  In  various 
conditions  in  which  excess  of  fluid  accumulates  in  the  body,  pilocarpine 
may  be  exhibited  to  remove  it.  In  dropsy,  especially  that  due  to  renal 
disease,  a  few  injections  frequently  reduce  the  fluid  and  remove  the 
effects  of  the  accumulation,  although  they  do  not,  of  course,  affect  the 
diseased  tissues  directly.  By  unburthening  the  blood  and  tissues  of 
their  excessive  fluid,  however,  pilocarpine  may  improve  the  nutrition 
of  the  kidney,  and  thereby  promote  its  recovery.  In  dropsy  due  to 
heart  disease  pilocarpine  must  be  used  with  caution,  owing  to  its  action 
on  the  heart.  In  some  other  exudations  pilocarpine  has  also  been 
advised,  as  in  pleural,  pericardial,  and  subretinal  effusion.  It  must 
be  remembered  that  after  the  diaphoresis  produced  by  pilocarpine  there 
usually  sets  in  a  period  of  depression,  weakness  and  languor,  and  this 
may  be  sufficient  to  counteract  the  improvement  obtained  by  the 
removal  of  the  fluid.  It  is  still  a  disputed  point  whether  pilocarpine 
possesses  any  advantage  as  a  sudorific  over  the  other  means  of  producing 
sweating,  such  as  hot  or  cold  packs.  Its  advocates  point  to  the  fact 
that  much  less  disturbance  of  the  patient  is  required,  and  that  the 
subsequent  depression  is  not  greater,  while  its  opponents  assert  that  the 
hot  or  cold  pack  produces  less  depression  and  is  not  accompanied  by  the 
unpleasant  salivation  and  occasional  nausea  of  pilocarpine.  Accumu- 
lations of  fluid  in  the  body  may  also  be  removed  by  way  of  the  bowel  by 
the  use  of  a  hydragogue  cathartic  or  preferably  a  saline  purgative,  or 
the  kidney  may  be  stimulated  to  special  activity  by  the  use  of  such 
diuretics  as  theobromine  and  caffeine.  The  last  method  of  treatment  is 
that  generally  preferred  as  it  induces  less  weakness  and  depression 
subsequently  than  either  of  the  others.  The  sweating  induced  by 
pilocarpine  is  much  more  profuse  than  that  seen  after  the  nauseating 
diaphoretics  such  as  ipecacuanha,  and  no  such  effects  are  claimed  for 
pilocarpine  as  for  these  in  chills  and  fever. 

In  uraemia  pilocarpine  sometimes  proves  of  great  benefit  if  exhibited 
early,  and  it  has  been  supposed  that  this  w^as  due  to  the  skin  taking 
up  the  renal  function  vicariously  and  eliminating  the  poison.     Some 


344  SUBSTANCES  ACTING  AFTER  ABSORPTION 

supi^ort  has  been  given  this  explanation  by  the  discovery  of  traces  of 
urea  in  the  perspiration  after  pilocarpine,  but  it  is  now  recognized  that 
tlie  urea  is  not  the  poisonous  principle  in  ura'niia,  and  the  beneficial 
effects  are  probably  due  rather  to  the  removal  of  fluid  and  the  relief 
of  the  overstrained  circulation.  It  has  also  been  suggested  that  pilo- 
carpine acts  directly  on  the  kidney,  and  an  increase  in  the  urine  is  not 
iiifrc(iuently  seen  after  several  injections;  but  this  is  to  be  ascribed 
rather  to  the  changes  in  the  circulation  following  the  removal  of  the 
fluid  than  to  any  direct  action  on  the  renal  epithelium,  for  which  there 
does  not  exist  any  satisfactory  experimental  evidence. 

Tn  ophthalmic  surgery  pilocarj)ine  has  been  em])loyed  as  a  substitute 
for  physostigmine,  to  contract  the  pupil  and  reduce  the  intraocular 
pressure.  For  this  purpose  a  very  dilute  solution  of  the  salts  (2  per 
cent.)  may  be  used,  or  gelatin  lamellae  may  be  prescribed,  each 
containing  j  mg.  (2Z()  gr.),  to  be  laid  on  the  conjunctiva.  The  con- 
traction of  the  pupil  generally  attains  its  maximum  in  about  h-l  hour, 
and  j)asses  off  in  3-5  hours;  it  is  generally  less  comi)lete  and  of  shorter 
duration  than  that  seen  after  physostigmine.  Pilocarpine  is  said  to 
first  increase  and  then  lower  the  intraocular  tension. 

In  various  diseases  of  the  ear,  pilocarpine  has  been  used  with  good 
effects  in  some  cases,  but  it  is  quite  unknown  how  it  acts  here.  The 
conditions  in  which  it  is  of  service  are  Narious  forms  of  labyrinthine 
disease,  and  some  forms  of  effusion  into  the  tympanic  cavity. 

Pilocarpine  was  at  one  time  used  to  cause  contractions  of  the  uterus 
in  labor,  and  several  cases  of  abortion  have  been  ascribed  to  its  use. 
Further  experience  has  led  to  the  conclusion,  however,  that  in  order 
to  elicit  tliis  ecbolic  action  quantities  are  necessary  which  produce 
undesirable  secondary  symptoms. 

Pilocarpine  is  frequently  prescribed  in  lotions  for  the  hair,  and  a 
renewed  growth  of  the  hair  has  been  frecpiently  seen  in  alopecia  treated 
in  this  way.  This  has  been  explained  by  its  action  on  the  glands  of 
the  skin,  increasing  the  moisture  of  the  scalp  and  improving  its  circu- 
lation and  nutrition,  but  Tappeiner  found  that  the  local  application 
of  pilocarpine  to  the  skin  produces  no  increase  in  the  secretion  of  the 
glands. 

In  cases  of  atropine  poisoning,  the  use  of  pilocarpine  is  quite  unjusti- 
fied as  the  danger  arises  from  the  central  nervous  system  in  which  the 
action  of  atropine  is  not  antagonized  by  pilocarpine.  In  poisoning  from 
pilocarpine  or  nuiscarine  small  (piantities  of  atropine  are  the  antidote 
recommended  alike  by  pharmacological  experiment  and  l)y  clinical 
experience. 

Muscarine  Intoxication. — In  Siberia  the  Agaricus  muscarius  is  used  to 
form  an  intoxicating  beverage.  The  sym{)toms  produced  are  hilarity 
and  jollity,  and  the  victims  declare  themselves  to  be  more  capable 
of  fatiguing  exertions  than  they  would  lie  without  the  preparation, 
lucntually  giddiness  and  somnolence  are  produced,  and  after  large 
(piantities  \-oniiting  and  convulsive  attacks  may  follow  and  eventually 
proNc  fatal.    The  exhilarating  elfects  are  probably  due  to  the  presence 


PIIYSOSTIGMINE  345 

of  a  poison  discovered  by  Harmsen  and  not  to  tlie  nuiscarinc.  This 
new  poison  seems  to  play  a  role  at  least  as  ini])ortant  as  that  of  musca- 
rine in  cases  of  amanita  poisoning;  it  is  not  antagonized  hy  atr()i)ine, 
and  its  chemical  natnre  is  unknown. 

Bibliography.^ 
Muscarine. 

Schmicdeberg  u.  Koppe.     Das  Muscarin.     Leipzig,  1S69. 

Straub.     Pfliiger's  Arch.,  cxix,  p.  127. 

MacLean.     Biochem.  Jouin.,  iii,  p.  1;    iv,  p.  G6. 

Fleischhaucr.     Zeitschr.  f.  Biol.,  lix,  p.  262. 

Gaskcll.     Phil.  Trans.  Roy.  Soc,  1882.    Journ.  of  Physiol.,  iii,  iv,  viii. 

Dixon  and  Brodie.     Journ.  of  Phys.,  xxix,  p.  155. 

Harmsen.     Arch.  f.  exp.  Path.  u.  Pharm.,  1,  p.  361. 

Honda.     Arch.  f.  exp.  Path.  u.  Pharm.,  Ixiv,  p.  72;    Ixv,  p.  454. 

Schultz.     Arch.  f.  Anat.  u.  Phys.,  1898,  p.  73. 

Dale.     Journ.  of  Pharmacol,  vi,  p.  147. 

Pilocarpine. 

Langley.     Journ.  of  Anatomy  and  Physiol.,  x,  p.  187.     Journ.  of  Physiol.,  i,  iii. 

Luclisinger.     Pfluger's  Archiv,  xv,  p.  482;    xviii,  p.  501. 

Neukirch.     Arch.  f.  d.  ges.  Phys.,  cxlvii,  p.  153. 

Ringer  and  Murrell.     Journ.  of  Physiol.,  ii,  p.  135;    Practitioner,  xxvi,  p.  5. 

Albertoni.     Arch.  f.  exp.  Path.  u.  Pharm.,  xi,  p.  415. 

Harnack  u.  Meyer.     Arch.  f.  exp.  Path.  u.  Pharm.,  xii,  p.  366. 

Frank  u.  Voit.     Ztschr.  f.  Biol.,  xliv,  p.  111. 

Schlegel.     Arch.  f.  exp.  Path.  u.  Pharm.,  xx,  p.  271. 

Schiff.     Archiv.  f.  Verdauungskrh.,  vi,  p.  107. 

Marshall.     Journ.  of  Physiol.,  xxxi,  p.  120. 

Harvey.     Journ.  of  Physiol.,  xxxv,  p.  115. 

PdU.     Zeitschr.  f.  exp.  Path.,  vii,  p.  577.     (ArecoHne.) 

Xin.    PHYSOSTIGMINE. 

Physostigmine  or  Eserine  is  the  chief  alkaloid  of  the  Calabar  bean, 
or  Ordeal  bean  (Physostigma  venenosum),  which  grows  in  Western 
Africa  and  was  employed  there  by  the  natives  in  the  trials  by  ordeal 
for  witchcraft.  Either  physostigmine  itself,  or  a  nearly  allied  alkaloid, 
occurs  also  in  the  Kali  or  Call  nuts,  the  seeds  of  Mucuna  urens.  The 
constitution  of  physostigmine  (C15H21N3O2)  is  still  unknown.^ 

Physostigmine  produces  a  number  of  symptoms  resembling  those 
of  muscarine  and  pilocarpine  poisoning;  it  stimulates  the  same  organs, 
but  may  affect  another  set  of  receptors,  and  it  has  much  less  effect  on 
the  inhibitory  nerves. 

Symptoms. — The  symptoms  of  poisoning  vary  but  little  in  different 
animals;  in  the  dog  and  rabbit  the  first  results  of  a  large  dose  of 
physostigmine  are  weakness  in  the  voluntary  movements  and  a  curious 
tremor  and  muscular  twitching,  beginning  in  the  hind  legs,  but  soon 

'  The  literature  of  muscarine  and  pilocarpine  is  so  mixed  with  that  of  atropine,  nico- 
tine, and  physostigmine  that  a  complete  list  would  involve  numerous  repetitions.  I  must, 
therefore,  refer  those  interested  to  the  bibliography  given  under  those  groups,  and  shall 
mention  here  only  the  papers  which  deal  very  largely  with  muscarine  and  pilocarpine. 

2  A  number  of  other  alkaloids  have  been  stated  to  occur  in  Calabar  bean,  but  their 
existence  is  not  sufficiently  established  in  most  cases  and  nothing  is  known  of  their  action. 
They  have  been  named  Calabarine,  Isophysostigmine,  Physovenine,  Eseramine,  etc. 


346       SUBSTANCES  ACTING  AFTER  ABSORPTION 

extending  over  the  whole  body.  The  animal  falls  on  one  side  and  can 
not  raise  itself  again,  althongh  it  makes  efforts  to  do  so  when  tonched. 
The  saliva  and  tears  are  increased,  the  bowel  is  often  evacuated  and 
in  the  dog  vonnting  is  connnon.  The  respiration  is  at  first  rapid 
and  deep,  and  later  slow  and  dyspnoeic,  the  heart  is  weak  and  slow, 
and  the  pupil  is  contracted  to  a  small  point.  These  symptoms  become 
more  marked  as  more  of  the  poison  reaches  the  blood,  until  the  respi- 
ration ceases.  In  cats  these  symptoms  of  depression  and  paralysis 
are  preceded  by  a  stage  of  increased  movement  and  evident  anxiety, 
but  the  later  symptoms  resemble  those  in  the  dog.  In  man  physostig- 
mine  elicits  practically  the  same  results  as  in  the  dog,  vomiting  and 
pain  in  the  stomach  region,  dyspncjea,  giddiness  and  muscular  weak- 
ness, contraction  of  the  i)upil,  salivation,  and  perspiration.  The  heart 
is  slow,  muscular  twitching  may  be  present  and  complete  collapse 
follows.  In  frogs  the  voluntary  movements  disappear  soon  after  the 
injection  of  physostigmine,  the  respiration  ceases,  and  last  of  all  the 
reflexes  are  paralyzed. 

Central  Nervous  System. — In  cases  of  poisoning  in  man,  the  conscious- 
ness is  preserved  until  late,  which  indicates  that  the  highest  functions 
of  the  brain  are  not  directly  affected  by  physostigmine.  The  motor 
cerebral  cortex  is  apparently  rendered  more  excitable,  for  in  epileptics 
the  number  and  intensity  of  the  seizures  increase  under  its  use,  and  in 
guinea-pigs  rendered  epileptic  by  operative  procedures  the  same  aggra- 
vation is  seen  after  it.  In  the  dog  epileptiform  convulsions  occur 
occasionally,  while  in  the  cat  a  stage  of  excitement  is  generally  present. 
It  is  possible,  however,  that  some  of  these  effects  may  arise  from  the 
peripheral  action  of  the  poison,  for  example  from  the  partial  asphyxia 
from  broncho-constriction.  The  depression  and  muscular  weakness 
which  is  seen  in  animals  under  large  doses  probably  arise  from  aft'ection 
of  lower  parts  of  the  central  nervous  system  and  resemble  the  condition 
known  as  collapse  more  than  that  of  narcosis. 

The  muscular  twitching  seems  to  be  entirely  independent  of  the 
central  nervous  system,  for  it  is  not  prevented  by  division  of  the  motor 
nerves.  This  symptom  is  not  marked  in  frogs,  but  may  be  so  developed 
in  mammals  as  to  simulate  convulsions,  and  is  due  to  stimulation  of  the 
same  receptors  as  are  affected  by  curara,  as  is  shown  by  the  fact  that 
the  twitching  is  arrested  by  this  drug.  The  antagonism  between 
these  two  alkaloids  is  mutual,  for  the  paralysis  induced  by  curara 
may  be  removed  by  j)hysostigmine  applied  in  somewhat  large  doses, 
and  animals  may  thus  recover  from  (juantities  of  curara  which  would 
otherwise  prove  fatal.  Atropine  also  removes  these  movements,  ap- 
parently from  some  action  on  the  myoneural  receptors.  When  the 
nerve  to  a  muscle  has  been  divided  and  allowed  to  degenerate,  phy- 
sostigmine no  longer  causes  these  twitchings,  but  induces  a  slow  tonic 
contraction  which  disappears  under  curara  but  not  under  atropine 
(Ednnnids  and  Uoth). 

The  Respiration  is  at  first  somewhat  accelerated  and  then  becomes 
slow  and  wtak.     The  i>reliminary  acceleration  may  arise  from  central 


I 

f 


PHYSOSTIGMINE  347 

stimulation,  or  possibly  from  partial  asphyxia  due  to  constriction  of  the 
bronchi.  The  sul)sc(iucnt  weakness  and  slowness  of  the  })reathing  is 
undoubtedly  of  central  orioin,  and  death  follows  from  the  failure  of  the 
respiratory  centre. 

The  changes  in  the  Circulation  reciuire  further  investigation.  Small 
doses  slow  the  pulse  and  increase  the  blood-pressure,  while  larger  are 
followed  by  greater  slowing  of  the  heart  and  a  fall  in  the  blood-pressure. 
The  slowness  of  the  pulse  is  due  to  the  poison  acting  on  the  heart  directly 
and  not  to  any  inhibitory  interference,  for  it  occurs  after  large  quantities 
of  atropine.  According  to  several  observers,  the  irritability  of  the 
terminations  of  the  inhibitory  fibres  in  the  heart  is  increased,  so  that 
stimulation  of  the  ^•agus  is  more  effective  after  physostigmine.  The 
contractions  of  the  heart  do  not  seem  to  be  altered  in  strength  in  mam- 
mals, though  the  rhythm  is  slower. 

The  increased  blood-pressure  has  also  been  the  subject  of  some  dis- 
cussion. It  seems  independent,  in  part  at  least,  of  the  vasomotor 
centre,  for  it  is  not  prevented  by  section  of  the  spinal  cord  or  of  the 
splanchnic  nerves,  operations  which  prevent  impulses  from  the  centre 
reaching  the  vessels.  It  may  be  partly  due  to  the  powerful  contraction 
of  the  intestines  expelling  the  blood  from  the  mesenteric  area,  or  to 
direct  action  on  the  muscular  coats  of  the  arterioles  causing  contraction 
and  thus  narrowing  their  calibre,  or  perhaps  to  both  of  these,  along 
with  some  increase  in  the  activity  of  the  vasomotor  centre. 

The  frog's  heart  beats  more  slowly  after  physostigmine,  but  here 
the  individual  contractions  are  said  to  be  strengthened  and  prolonged, 
and  there  is  definite  evidence  of  stimulation  of  the  heart  muscle,  which 
is  not  seen  in  mammals.  If  the  vagus  be  stimulated  in  the  frog  after 
physostigmine,  it  produces  slowing  but  no  complete  standstill  of  the 
heart,  because  the  irritability  of  the  muscle  is  so  much  augmented  that 
the  inhibitory  apparatus  can  no  longer  entirely  control  it.  If  such 
a  poison  as  muscarine  produces  complete  standstill,  physostogmine 
removes  it,  not  by  depressing  the  inhibitory  apparatus,  but  by 
increasing  the  irritability  of  the  muscle. 

The  Secretions  are  increased  by  physostigmine  as  by  pilocarpine 
and  muscarine;  thus  the  saliva,  the  tears,  the  perspiration,  the  mucus 
secretion  and  the  pancreatic  juice  are  all  augmented. 

Muscle. — Physostigmine  produces  powerful  contractions  of  the 
Stomach,  Intestine  and  Uterus,  Ureter,  Bladder,  Spleen  and  Bronchial 
Mnscle  exactly  resembling  those  elicited  by  muscarine  and  pilocarpine. 
It  differs  from  these,  however,  in  not  acting  on  the  inhibitory  nerves  of 
the  uterus. 

The  Intraocnlar  Muscles  also  undergo  contraction,  and  their  move- 
ments under  physostigmine  have  been  the  subject  of  a  large  number  of 
investigations  and  of  a  good  deal  of  controversy.  The  pupil  contracts 
when  physostigmine  is  employed  either  locally  or  internally,  and 
this  contraction  may  be  lessened  by  the  subsequent  application  of 
atropine,  but  is  not  altogether  removed  except  by  large  quantities. 
On  the  other  hand,  the  dilatation  of  the  pupil  produced  by  small  quanti- 


348  SUBSTANCES  ACTING  AFTER  ABSORPTION 

ties  of  atropine  may  be  diminished  by  physostijjmine,  l)ut  tlie  resulting; 
contraction  is  much  less  than  that  caused  by  i)hysostogmiiie  appHed 
to  the  normal  eye.  The  ciliary  nuiscle  is  acted  on  in  the  same  way  as 
the  iris,  so  that  the  eye  becomes  acconunodated  for  near  distance,  and 
atropine  induces  the  same  modifications.  The  effects  of  physostigmine, 
then,  on  the  secretory  organs,  pupil  and  ciliary  muscle  are  strictly 
analogous,  and  are  generally  attributed  to  the  alkaloid  stimulating  the 
terminations  of  the  nerves  in  these  organs.  Physostigmine  does  not  con- 
tract the  pupil  after  degeneration  of  the  motor  oculi  nerve  (Anderson), 
which  apparently  involves  its  receptor;  it  is  suggested  that  physostig- 
mine acts  on  the  terminations  of  the  nerves  in  the  iris,  while  pilocarpine 
and  atropine,  which  act  after  degeneration,  affect  some  receptor  between 
these  and  the  actual  contractile  substance.  The  antagonism  of  phy- 
sostigmine to  atropine  is  more  complete  than  that  of  pilocarpine,  for  a 
renewal  of  the  contraction  can  be  elicited  more  easily  by  the  former 
alkaloid.  The  intraocular  pressure  is  reduced  by  the  application  of 
physostigmine  to  the  eye  and  this  has  generally  been  attributed  to  the 
contraction  of  the  pupil  facilitating  the  escape  of  the  fluid  by  allowing 
it  freer  access  to  the  spaces  of  Fontana.  Another  factor  may  be  contrac- 
tion of  the  intraocular  vessels,  which  lessens  the  secretion.    (Gronholm.) 

Peripheral  Action. It  has   been  discussed  whether  physostigmine 

actually  stimulates  the  myoneural  junctions,  that  is,  causes  impulses 
to  be  emitted  by  them  as  pilocarpine  does,  or  whether  it  merely  renders 
them  more  sensitive  to  stimuli  descending  the  nerve  fibres;  the  latter 
seems  to  be  the  case  in  some  instances,  for  it  is  found  that  when  the 
chorda  tympani  nerve  is  cut  physostigmine  often  fails  to  cause  secretion, 
though  electrical  stimulation  of  the  nerve  is  more  efficient  than  before. 
In  other  instances  physostigmine  appears  to  act  after  the  impulses 
from  above  are  excluded,  so  that  here  it  has  the  same  action  as  pilo- 
carpine. It  is  possible  that  the  failure  of  physostigmine  to  contract 
the  pupil  after  degeneration  of  the  postganglionic  ciliary  branches  may 
be  due  to  the  exclusion  of  the  impulses  from  the  centres  (Loewi  and 
Mansfeld). 

Some  physostigmine  is  Excreted  in  the  urine,  but  most  of  that 
ingested  is  destroyed  in  the  tissues.  It  has  also  been  found  in  the 
saliva  and  bile. 

The  symptoms  of  poisoning  with  Calabar  bean  are  identical  with 
those  caused  by  physostigmine,  except  when  an  old  preparation  is 
used,  when  some  stimulation  of  the  spinal  cord  may  be  induced. 

Preparations. 

Physostigmin^e  Salicylas,  escrine  saUcj^ate  (U.  S.  P.),  0.001  G.  (j^.V  gr.). 
PHYsosTiGMiNyE  SuLPHAS,  escrluc  suli)hate  (U.  S.  P.,  B.  P.),  0.001  G.  (/f  gr.); 

B.  P.,  ,.,W.  gr. 

Laniellce  Physostigmince  (B.  P.),  eacli  containing  |„'„„  gr.  ot  pliysostiginini' 
sulphate. 

The  sulphate  and  salicylate  of  phj^sostigniiue  arc  colorless  or  faintly  yi'llow 
crystals,  without  odor,  but  possessing  a  bitter  taste.  The  suli)hatc  is  dcliciiu's- 
cent  ill  tlie  air  and  is  very  soluble  in  both  alcoliol  and  water.     The  salicylate  is 


f 


PIl  YSOS TIG  MINE  349 

not  deliquescent,  has  usually  a  slight  acid  reaction,  and  is  soluble  in  150  parts 
of  cold,  or  30  parts  of  boiling  water.  Both  salts  undergo  decomposition  when 
kept  in  solution  and  then  assume  a  reddish-brown  color;  the  addition  of  boric 
or  suljihurous  acid  to  the  solution  is  said  to  retard  this  decomposition. 

Therapeutic  Uses. — In  recent  years  physostigmine  has  been  given  in  i)ills 
or  hyi)odernncally  (^;V  gr.)  in  cases  of  atony  of  the  intestine  leading  to 
tympanitis  and  meteorism.  Bnt  it  is  chiefly  used  for  its  action  on  the 
intraocular  muscles  and  tension.  For  this  purpose  a  solution  of  ^-1 
per  cent,  is  dropped  in  the  eye,  2-4  drops  at  a  time,  or  small  discs  of 
gelatin  impregnated  with  the  alkaloid  may  be  applied  to  the  conjunc- 
tiva (B.  P.).  The  pupil  begins  to  contract  in  5-15  minutes,  and  attains 
its  smallest  size  in  half  an  hour.  It  remains  contracted  12-14  hours, 
and  according  to  some  observers  a  difference  in  the  size  of  the  two 
pupils  may  be  made  out  for  several  days.  The  ciliary  muscle  contracts 
along  with  the  iris,  and  the  eye  becomes  accommodated  for  short 
distances.  This  action  on  the  accommodation  passes  off  in  2-4  hours, 
but  the  sight  is  often  rendered  indistinct  for  some  hours  longer  by 
alternate  contraction  and  relaxation  of  the  ciliary  muscle.  The  action 
of  physostigmine  on  the  eye  differs  from  that  of  muscarine,  for  the 
former  acts  more  on  the  pupil,  the  latter  on  the  ciliary  muscle,  and  the 
pupil  is  often  contracted  by  physostigmine  while  the  accommodation 
is  practically  unchanged.  The  intraocular  pressure  is  somewhat  in- 
creased at  first  and  subsequently  sinks.  Its  action  in  narrowing  the 
pupil  after  atropine  has  been  made  use  of  to  remove  the  dilatation 
produced  so  frequently  in  ophthalmic  surgery,  but  homatropine  and 
hyoscine,  which  produce  a  shorter  mydriasis  than  atropine,  have  almost 
driven  it  from  the  field.  It  antagonizes  the  dilatation  of  the  pupil 
after  homatropine  and  cocaine  much  more  successfully  than  that  due 
to  atropine.  It  has  also  been  used  in  cases  of  synechia  (attachment 
of  the  iris  to  the  lens)  alternately  with  atropine.  The  alternate  con- 
traction and  dilatation  of  the  pupil  would,  it  was  hoped,  break  down 
the  attachment,  but  the  condition  is  now  generally  treated  by  operation. 

Physostigmine  is  now  chiefly  employed  to  reduce  the  intraocular 
pressure  in  glaucoma. 

Bibliography. 

Eraser.     Edinburgh  Medical  Journal,  ix,  p.  36,  1864.     Journal  of  Anat.  and  Physiol., 
1867,  p.  323.     Practitioner,  iv,  p.  65. 

Amslein  u.  Sustschinsky .     Untersuch.  a.  d.  physiol.  Laborator.  zu  Wiirzburg.  ii,  p.  81. 

Rogow.     Ztschr.  f.  rationcUe  Heilkunde,  xxix,  p.  1. 

Heidenhain.     Pfluger's  Arch.  f.  Physol.,  v,  p.  309. 

Laschkeivich.     Virchow's  Archiv,  xxxv,  p.  291. 

Harnack  u.  Wiikowski.     Arch.  f.  exp.  Path.  u.  Pharm.,  v,  p.  401. 

Harnack  u.  Meyer.     Ibid.,  xii,  p.  366. 

Turtschaninow.     Ibid.,  xxxiv,  p.  208. 

Heubner.     Ibid.,  liii,  p.  313. 

Edmunds  and  Roth.     Amer.  Journ.  of  Physiol.,  xxiii,  p.  28. 

Anderson.     Journ.  of  Phys.,  xxxiii,  p.  414. 

Hedbom.     Skandinav.  Arch.  f.  Physiol.,  viii,  p.  209. 

Schuliz.     Arch.  f.  [Anat.  u.]  Phys.,  1898,  p.  66. 

Rothberger.     Pfluger's  Arch.,  Ixxxvii,  p.  117. 

Grunholm.     Arch.  f.  Ophthalmol.,  xlix,  p.  620. 

Loewi  u.  Mansfeld.     Arch.  f.  exp.  Path.  u.  Pharm.,  Ixii,  p.  180. 


350  SUBSTANCES  ACTING  AFTER  ABSOIU'TION 


XIV.    COCAINE. 

Cocaine  is  a  comparatively  recent  addition  to  therapeutics,  although 
the  coca  plant  has  been  in  use  in  South  America  for  centuries.  It  is 
indigenous  there,  but  has  been  introduced  into  India,  Ceylon  and 
Java.  The  leaves  of  the  coca  grown  in  Peru  and  Bolivia  contain 
cocaine  along  with  small  quantities  of  other  alkaloids,  but  the  Indian 
coca  and  still  more  the  Java  leaves  contain  a  smaller  proportion  of 
cocaine  and  a  larger  amount  of  the  less  known  alkaloids. 

Cocaine,  like  atropine,  is  readily  decomposed  into  several  constit- 
uents. On  heating  it  with  water,  methyl  alcohol  is  thrown  off,  leaving 
Benzoyl-eccjonine,  which  may  be  further  broken  up  into  benzoic  acid 
and  Ecgonine. 

Ecgonine.                                                               Cocaine. 
CH2— CH CH'COOH  CH2— CH CH-CQ-OCHa 


N(CH3)CH-0H 
CHr-CH CH2  CH2— CH CH; 


N(CH)3CH-0-CO-C6H6  •* 


Many  artificial  cocaines  have  been  formed  by  substituting  other  radicles  for 
the  methyl  or  benzojd  in  this  formula,  and  several  of  these  have  since  been 
found  in  the  cultivated  plant,  as  for  example  Cinncunyl-cocaine,  in  which  cin- 
namyl  occupies  the  position  of  benzo3'l  in  the  above  formula.  Various  other 
alkaloids,  such  as  Cocamine,  Isococamine,  Homococmnine,  and  Homoisococamine 
are  also  present;  all  of  these  contain  the  ecgonine  molecule  in  combination 
with  various  acids,  and  cocaine  may  be  formed  from  all  of  them  bj^  isolating 
the  ecgonine  and  combining  it  with  benzoic  acid  and  methjd.  These  alkaloids 
are  present  in  the  plant  in  very  small  quantities  compared  with  cocaine  and 
have  not  been  used  therapeuticallj^  Another  alkaloid  which  has  been  found 
in  the  Java  coca  is  Tropacocaine,  which  is  a  combination  of  benzoic  acid  and  a 
base  (CgHisNO).  It  will  be  observed  that  the  fornmla  of  ecgonine  resembles 
very  closely  that  of  tropine,  each  containing  the  same  nucleus,  t)ut  differing 
slightly  in  the  radicles  attached  to  it. 

The  most  important  effects  of  cocaine  are  those  on  the  central  nervous 
system  and  on  the  sensory  nerves. 

Symptoms. — The  symptoms  of  cocaine  poisoning  in  man  vary  a  good 
deal  in  did'erent  individuals.  In  most  cases  small  quantities  produce 
some  excitement,  i)leasurable  or  disagreeable.  The  i)atient  is  generally 
restless  and  more  garrulous  than  in  ordinary  life,  often  somewhat 
anxious  and  confused.  But  very  often  a  small  dose  is  followed  by  a 
calm,  languorous  state,  somewhat  resembling  that  induced  by  small 
Cjuantities  of  morphine,  but  dift'ering  from  it  in  there  being  less  tendency 
to  sleep.  The  pulse  is  accelerated,  the  respiration  is  quick  and  deep, 
the  pupil  generally  dilated,  and  headache  and  dryness  of  the  throat 
are  complained  of.  The  reflexes  may  be  found  somewhat  more  easily 
excited  than  usual  and  tremors  or  slight  convulsive  movements  often 
occur;  tonic  or  clonic  convulsions  sometimes  supervene  later,  the 
heart  becomes  extremely  accelerated,  the  breathing  becomes  rapid 
and  dynpna'ic  and  may  be  finally  arrested  during  a  convulsion.  In 
most  cases  the  convulsive  seizures  are  entirely  absent,  however,  and 


I 


COCAINE  351 

fainting  and  collapse  occur,  apparently  from  the  rapid  absorption 
of  a  large  dose.  The  skin  is  cyanotic  and  cold,  the  heart  slow  and 
weak;  the  respiration  is  very  much  depressed  and  death  follows  from 
its  gradual  cessation.  Vomiting  is  occasionally  seen  at  an  early  stage, 
but  is  not  by  any  means  common. 

In  the  dog,  cat  and  rabbit  the  symptoms  are  invariably  those  of 
stimulation  of  the  central  nervous  system.  Soon  after  the  injection 
the  animal  shows  symptoms  of  great  restlessness  and  excitement;  it 
seems  unable  to  keep  still,  the  dog  at  first  showing  all  the  signs  of 
affection  and  excitement  which  he  displays  on  ordinary  occasions  on 
being  unchained  or  taken  for  a  walk,  but  afterward  running  contin- 
ually in  a  circle  and  paying  but  little  heed  to  anything  around  him. 
Still  later  regular  convulsions  occur,  and  these  are  at  first  clonic,  but 
may  afterward  become  tonic,  and  then  resemble  those  seen  in  strych- 
nine poisoning.  Even  before  the  convulsions  appear  the  animal  seems 
partially  unconscious,  and  in  the  intervals  between  them  he  lies  in  an 
apathetic  state,  which  soon  deepens  to  coma  and  death  from  asphyxia. 

In  the  frog  a  certain  amount  of  stimulation  of  the  central  nervous 
system  is  often  displayed  after  small  doses — increased  movement, 
exaggerated  reflex  and  occasionally  convulsions — but  these  soon  pass 
into  depression  and  eventually  total  paralysis  of  the  central  nervous 
system,  while  the  peripheral  nerves  still  maintain  their  functions. 

General  Action. — Many  of  these  symptoms  point  to  a  stimulant 
action  on  the  Central  Nervous  System,  resembling  closely  that  seen  in 
atropine  poisoning.  Thus  the  garrulity  which  is  so  often  produced 
by  cocaine  indicates  an  increased  activity  of  the  cerebrum,  and  the 
increased  movement  in  the  lower  animals  distinctly  points  to  an  affec- 
tion of  this  part  of  the  brain,  for  the  movements  are  perfectly  coordi- 
nated, and,  in  fact,  in  the  early  stages  resemble  exactly  those  performed 
by  the  normal  animal  in  a  condition  of  excitement.  Further  evidence 
of  the  action  of  cocaine  on  the  cerebrum  is  offered  by  its  effects  on 
muscular  work.  The  natives  of  Peru  and  Bolivia  have  used  it  for 
centuries  to  increase  their  endurance  of  fatigue.  The  bearers  of  the 
Andes,  for  example,  march  for  hours  and  days  with  very  little  rest  or 
food  when  they  are  supplied  with  coca  leaves  to  chew.  The  effects  of 
cocaine  on  the  muscular  power  and  on  fatigue  have  been  investigated 
also  by  means  of  the  ergograph  and  dynamometer,  and  all  observers 
are  at  one  in  asserting  that  much  more  work  can  be  done  after  cocaine 
than  before  it,  and  that  it  has  a  surprising  potency  in  removing 
fatigue.  As  regards  mental  work,  its  effects  are  less  known,  but  on 
the  analogy  of  caffeine  it  may  be  supposed  to  increase  the  mental 
powers  also  when  taken  in  small  quantities.  Some  travellers  in  South 
America  relate  marvellous  tales  of  its  producing  feelings  of  the  highest 
bliss  and  power,  but  these  have  not  been  confirmed  by  experience  in 
the  action  of  cocaine  iji  less  romantic  regions  of  the  globe.  Cocaine 
in  small  quantities,  then,  increases  the  higher  functions  of  the  cere- 
brum, while  in  somewhat  larger  doses  the  stimulant  effect  spreads  to 
the  lower  areas  and   produces  a  very    great   increase  in  movement, 


\ 

352  SUBSTANCES  ACTIXG  AFTER  ABSORPTION  I  ( 


accompanied,  it  would  seem,  by  a  depression  of  the  consciousness. 
At  the  same  time,  the  coordinating  or  balancing  powers  seem  affected, 
so  that  the  animal  generally  moves  in  a  circle,  the  symptoms  resembling 
the  forced  movements  often  seen  in  affections  of  the  cerebellum. 

The  motor  areas  of  the  cerel)rum  have  been  found  to  be  more  easily 
stinuilated  by  the  electric  shock  \\hen  cocaine  is  injected,  though  when 
it  is  painted  on  the  surface  of  the  brain  it  lowers  the  irritability,  owing 
to  its  being  present  in  too  great  concentration.  Still  larger  quantities 
induce  convulsions,  which  are  not  of  spinal  origin,  but  point  rather  to 
action  on  some  undetermined  part  of  the  hind  brain.  At  an  early 
stage  the  medulla  oblongata  is  affected,  as  is  shown  by  the  quickened 
respiration,  and  the  exaggerated  reflexes  indicate  stimulation  of  the 
spinal  cord,  which  may  be  so  great  after  very  large  doses  as  to  cause 
convulsions  like  those  produced  by  strychnine.  The  action  of  cocaine 
on  the  central  nervous  system  is  primarily  a  descending  stimulation, 
the  cerebrum  being  first  affected,  then  the  hind  brain  and  medulla 
oblongata,  and  last  of  all  the  spinal  cord.  Perhaps  it  might  be  better 
expressed  by  saying  that  after  small  quantities  the  chief  symptoms 
arise  from  the  cerebrum,  but  as  the  dose  is  increased  those  from  the 
lower  parts  of  the  central  axis  tend  to  become  more  prominent.  After 
the  stimulation  there  succeeds  depression,  which  follows  the  stimu- 
lation downward,  affecting  first  the  cerebrum  and  then  the  lower 
divisions.  The  two  stages  are  not  definitely  divided,  however,  one 
part  of  the  cerebrum  often  showing  distinct  depression,  while  another 
is  still  in  a  condition  of  excessive  activity.  In  some  cases,  especially 
in  man,  when  a  large  dose  is  rapidly  absorbed,  the  stage  of  excitement 
may  be  very  short  or  apparently  absent  and  the  whole  course  of  the 
symptoms  then  points  to  medullary  depression. 

The  Respiration  after  cocaine  is  much  accelerated,  owing  to  central 
stimulation.  At  first  the  depth  of  the  movement  is  not  changed,  but 
as  the  acceleration  progresses  the  air  inspired  with  each  breath  grad- 
ually becomes  less.  During  the  convulsions  the  respiration  is  irregular 
or  ceases,  but  it  recovers  again  in  the  intervals,  until  after  a  very 
violent  paroxysm  it  fails  to  be  reinstated.  In  other  cases  the  breathing 
becomes  slower  and  weaker  after  a  time,  and  eventually  stops  from 
paralysis  of  the  centre.  Periodic  respiration  is  frequently  seen,  of  the 
form  generally  known  as  Cheyne-Stokes'.    (See  Morphine,  page  241). 

The  Circulation  is  altered  by  cocaine,  owing  to  its  action  on  the 
heart  and  on  the  vessels.  The  heart  is  much  accelerated  in  mammals, 
while  in  the  amphibians  this  is  less  often  observed.  The  quickening 
has  been  ascribed  to  paralysis  of  the  inhibitory  terminations,  but  this 
seems  not  to  be  the  case,  for  stimulation  of  the  vagus  slows  the  heart 
even  late  in  the  poisoning.  The  heart  is  accelerated,  then,  either  by 
direct  action  on  the  muscle  or  by  stimnlation  of  the  accelerator  mech- 
anism. It  is  often  slow  before  death,  but  ai){)arently  not  invariablv, 
and  this  is  jirobably  due  to  direct  action  on  the  muscle.  In  the  frog's 
heart  the  inhibitory  apparatus  is  paralyzed,  the  ganglia  being  aftected 
in  the  same  way  as  by  curara  and  other  drugs. 


COCAIXE  353 

The  vessels  are  much  contracted  in  the  earher  stages  of  poisoning, 
and  this,  together  with  the  increased  rate  of  the  heart,  leads  to  a  very 
considerable  rise  in  the  blood-pressure.  The  constriction  of  the  vessels 
seems  partly  due  to  stimulation  of  the  vaso-constrictor  centre,  and 
partly  to  a  direct  action  on  the  vessel  walls,  for  local  application  leads 
to  constriction  of  the  vessels  and  blanching  of  the  mucous  membranes. 
It  has  not  been  determined  as  yet  how  far  this  direct  action  on  the  vessel 
walls  affects  the  blood-pressure  when  cocaine  is  absorbed  or  when  it 
is  injected  intravenously.  The  blood-pressure  subsequently  falls,  from 
peripheral  action,  if  Anrep's  assertion  that  stimulation  of  the  splanchnic 
then  produces  no  further  rise  of  pressure,  be  correct. 

The  effects  on  the  peripheral  Nerves  and  Muscles  are  disputed,  for 
Mosso  states  that  small  quantities  increase  the  strength  of  the  muscular 
contractions  on  electrical  stimulation  both  in  man  and  animals,  while 
others  have  failed  to  obtain  any  such  effect. 

After  the  injection  of  cocaine,  Anrep  observed  marked  pallor  of  the 
Intestiiie  and  powerful  peristalsis,  while  very  large  doses  caused  dila- 
tation of  the  mesenteric  vessels,  and  lessened  the  movement  of  the 
bowel  probably  through  paralyzing  the  local  nervous  mechanism. 

The  Urine  is  sometimes  said  to  be  increased  by  cocaine,  while  in 
other  instances  its  injection  has  been  followed  by  total  anuria  lasting 
for  several  hours.  This  suggests  that  the  action  is  not  a  direct  one  on 
the  kidney,  but  is  caused  merely  through  the  changes  in  the  calibre 
of  the  vessels. 

The  other  Secretions  seem  rather  decreased  than  augmented,  Init  no 
very  marked  effects  are  produced  on  them. 

The  Temperature  generally  rises  in  cases  of  poisoning,  sometimes  as 
much  as  3-5°  C,  from  increased  heat  formation  caused  by  cerebral 
action.  Langlois  and  Richet  observed  that  the  higher  the  temperature 
of  the  animal  the  more  easily  were  convulsions  produced  by  cocaine 
and  the  more  severe  their  type. 

It  used  to  be  supposed  that  cocaine  retarded  the  Tissue  Change  and  that 
less  food  was  required  when  it  was  supplied.  Tliis  was  based  on  the  state- 
ment of  the  endurance  of  the  natives  of  South  America  when  they  were  allowed 
to  chew  coca  leaves,  and  on  the  discovery  that  the  leaves  also  allay  hunger  to 
some  degree.  But  the  increase  in  the  working  power  is  due  to  the  effects  on  the 
central  nervous  system,  while  the  craving  for  food  is  probably  lessened  owing 
to  the  cocaine  inclucing  numbness  of  the  sensor\-  nerves  of  the  stomach  through 
its  local  action.  Careful  investigation  has  failed  to  reveal  any  significant 
action  on  the  metabohsm  of  animals  except  when  large  quantities  were  given 
over  several  days,  when  the  utilization  of  the  protem  and  fats  was  found  to 
be  impaired. 

A  curious  effect  of  cocaine,  noted  by  Ehrlich  in  mice,  is  a  widespread  destruc- 
tion of  the  hepatic  cells,  which  become  infiltrated  with  fat  and  often  undergo 
necrosis. 

Some  cocaine  is  Excreted  by  the  kidney  in  the  dog,  and  in  the  rabbit 
nearly  the  whole  of  that  ingested  may  reappear  in  the  urine,  the  tissues 
seeming  to  have  little  or  no  power  of  destroying  it  in  this  animal.    It  is 
23 


354  SUBSTANCES  ACTING  AFTER  ABSORPTION 

unknown  whether  it  is  excreted  in  man,  who  is  much  more  susceptible 
to  its  action  than  these  animals. 

Tolerance  is  said  to  be  attained  in  man  when  cocaine  is  taken  habit- 
ually, but  this  is  not  satisfactorily  established.  In  animals  repeated 
injection  leads  to  a  cumulation  of  cocaine  in  the  tissues  and  hence  the 
animal  instead  of  becoming  more  tolerant  becomes  more  susceptible  to 
each  new  injection.  As  the  concentration  in  the  body  increases,  the 
amount  in  the  urine  rises  (Grode). 

Local  Action. — Cocaine  applied  locally  in  most  parts  of  the  body 
])r()(luccs  a  loss  of  sensation  through  its  paralyzing  the  Terminations  of 
some  of  the  Sensory  Nerves,  particularly  those  conveying  impressions 
of  pain  and  touch.  The  exact  researches  of  Kiesow  show  that  heat 
and  cold  are  recognized  as  readily  as  in  the  unaffected  parts  of  the 
body.  Cocaine  applied  to  the  tongue  removes  the  taste  of  bitter  sub- 
stances, while  sweet  and  acid  fluids  lose  their  taste  only  partially, 
and  salt  is  recognized  as  easily  as  usual. ^  A  solution  applied  to  the 
nasal  mucous  membrane  paralyzes  the  sense  of  smell  entirely. 

The  ansesthesia  or  insensibility  to  pain  and  touch  may  be  induced  in 
any  of  the  mucous  membranes  that  can  be  reached  by  cocaine  in  suffi- 
cient concentration — pharynx,  larynx,  oesophagus,  stomach,  nose,  eye, 
urethra,  bladder,  vagina,  and  rectum.  Applied  to  the  unbroken  skin  its 
effects  are  less  marked,  as  it  penetrates  but  slowly  through  the  horny 
epidermis;  but  when  the  epidermis  is  removed  by  abrasions  or  by  skin 
disease,  the  cutaneous  organs  of  sensation  are  acted  on  in  the  same 
way  as  those  of  the  mucous  membranes.  The  deeper  sensory  termi- 
nations can  also  be  acted  on  by  hypodermic  injection,  which  causes  a 
feeling  of  numbness  and  the  relief  of  pain  in  the  part.  Hypodermic 
injection  reaches  not  only  the  nerve  terminations  of  the  subcutaneous 
tissues,  but  also  the  finer  nerve  bundles,  and  these  too  are  rendered 
insensible  as  far  as  the  solution  extends  to  them.  The  part  may  there- 
fore be  cut  into  or  be  subjected  to  other  surgical  treatment  without 
pain,  as  long  as  the  knife  does  not  pass  beyond  the  area  to  which  the 
drug  has  penetrated,  and  numbers  of  grave  surgical  operations  have 
been  performed  under  the  local  anaesthesia  produced  by  cocaine. 

Injected  into  the  neighborhood  of  a  nerve  trunk,  cocaine  penetrates  into 
the  fibres  and  induces  anaesthesia  of  the  organs  supplied  by  the  nerve, 
and  injected  into  the  spinal  canal  it  causes  annesthesia  over  large  areas 
of  the  body,  sometimes  o\'er  almost  the  whole  body,  from  its  acting  on 
the  posterior  roots  of  the  cord.  It  must  be  noted  that  the  amesthesia 
is  only  produced  by  the  local  application  of  the  drug.  The  internal 
administration  only  leads  to  a  partial  loss  of  sensation  in  the  throat 
and  stomach,  and  no  anaesthesia  is  induced  by  its  action  after  it  reaches 
the  bloodvessels.    The  reason  for  this  evidently  is  that  in  order  to  par- 

•    A  curious  contrast  is  presented  in  this  respect  by  gymneinic  acid,  which  is  obtained 
from  the  Gynuiema  siK'cstre,  and  which  removes  the  sensation  of  sweetness,  whiU;  "bitter" 
is  less  affected  and  "acid"  and  "salt"  arc  recognized  as  readily  as  usual.    Gymneniic  acid 
does  not  affect  any  other  sense  organs,  as  far  as  is  known,  and  is,  in  fact,  devoid  of  interest  ^ 
except  as  regards  its  efTcct  on  taste.  J 


COCAINE  355 

;il\  ze  the  sensory  fibres  and  terminations  a  considerable  amount  of  the 
drug  is  required,  but  much  less  is  necessary  to  paralyze  the  central 
nervous  system.  Even  in  the  frog  the  sensory  terminations  are  not 
fully  paralyzed  until  all  symptoms  of  reflex  excitability  have  disappeared 
and  total  {)aralysis  has  supervened. 

Cocaine  applied  to  a  nerve  trunk  proves  to  have  a  distinct  selective 
action,  for  the  sensory  fibres  fail  to  conduct  sensory  impressions,  while 
motor  impulses  pass  through  the  fibres  without  difficulty.  Similarly, 
when  it  is  injected  into  the  spinal  canal,  complete  loss  of  sensation 
in  the  lower  part  of  the  body  follows,  but  the  movements  are  almost 
unimpaired.  This  selection  is  only  relative,  for  larger  quantities 
paralyze  the  motor  nerve  fibres  also;  no  explanation  has  been  given  for 
this  difference  in  the  reaction  of  the  two  sets  of  fibres. 

When  cocaine  is  applied  locally  to  a  mucous  membrane  it  produces, 
besides  a  loss  of  sensation,  a  feeling  of  constriction  and  a  distinct 
pallor  and  contraction  of  the  vessels,  which  point  to  a  local  action  on 
the  vessel  walls. 

The  anjesthesia  produced  by  cocaine  is  comparatively  short,  but 
varies  with  the  strength  of  the  solution  applied  and  with  the  vascu- 
larity of  the  part;  as  soon  as  the  cocaine  is  absorbed,  the  local  action 
disappears  and  sensation  returns. 

Cocaine  is  applied  to  the  Eye  more  frequently  than  to  any  other 
part.  It  produces  local  anaesthesia  here,  along  with  contraction  of  the 
conjunctival  ^'essels,  and  this  is  followed  by  dilatation  of  the  pupil  and 
often  by  partial  loss  of  the  power  of  accommodation.  The  dilatation 
of  the  pupil  is  much  less  than  that  produced  by  atropine,  and  differs 
from  it  in  several  respects.  Thus,  the  light-reflex  is  preserved,  the 
pupil  contracting  in  bright  light  and  dilating  further  in  the  dark;  a 
number  of  drugs  which  have  little  or  no  effect  after  atropine,  contract 
the  cocainized  pupil  (pilocarpine,  muscarine,  physostigmine),  while 
atropine  dilates  it  still  further,  and  cocaine  produces  some  dilatation 
after  the  full  atropine  action  has  been  elicited.  It  is  evident,  then, 
that  the  two  drugs  produce  dilatation  b}'  acting  on  different  mechan- 
isms, and  the  great  majority  of  investigators  now^  hold  that  it  stimu- 
lates the  terminations  of  the  dilator  fibres  (Fig.  33).  The  motor  oculi 
is  not  involved  in  its  effects,  unless  very  large  quantities  are  applied, 
when  its  terminations  may  be  depressed  in  the  same  way  as  by  atropine 
(Schultz).  A  strong  argument  in  favor  of  the  view  given  above  has 
been  found  in  the  observation  that  when  the  dilator  nerves  degenerate, 
owing  to  removal  of  the  superior  cervical  ganglion,  cocaine  fails  to 
cause  dilatation  of  the  pupil. 

Several  other  symptoms  are  produced  by  the  local  application  of 
cocaine  to  the  eye,  at  any  rate  in  some  instances.  Thus,  the  vessels 
of  the  conjunctiva  are  much  constricted,  the  eye  is  more  widely  open 
than  usual,  so  that  the  white  sclerotic  is  seen  above  and  below  the 
iris;  the  whole  eyeball  is  pushed  forward  (exophthalmos),  and  the  intra- 
ocular tension  is  said  to  be  considerably  reduced.  All  of  these  features 
are  produced  only  after  cocaine  has  been  applied  in  considerable  quantity 


35G 


SUBSTANCES  ACTING  AFTER  ABSORPTION 


and  for  some  time,  and  may  be  due,  at  any  rate  in  part,  to  its  absorp- 
tion. They  may  all  be  observed  in  the  unpoisoned  animal  when  the 
cervical  sympathetic  trunk  is  stimulated,  and  arise  from  a  special 
action  of  cocaine  on  the  terminations  of  this  nerve.  All  of  these  symp- 
toms, except  the  anaesthesia  and  tiie  pallor  of  the  conjunctiva  and  iris, 
are  produced  by  the  injection  of  cocaine  as  well  as  by  its  local  applica- 


Diagram  of  the  innervation  of  the  iris.  P,  a  fibre  of  the  motor  ocuH  passing  from  the 
brain  to  the  ciHary  ganghon  A^,  in  which  it  terminates  around  a  nerve  cell,  which  sends 
an  axis  cylinder  to  terminate,  AI,  in  the  circular  fibres  of  the  iris.  R,  a  spinal  nerve  fibre 
issuing  from  the  lower  cervical  cortl,  rvinning  through  the  stellate  and  inferior  cervical 
ganglia  and  terminating  around  a  ganglion  cell  in  the  superior  cervical  ganglion,  G.  The 
axis  cylinder  from  this  nerve  cell  runs  to  the  iris  (passing  the  ciliary  ganglion)  and  ter- 
minates in  fibrils  C,  on  the  radiating  fibres.  C  is  the  point  which  cocaine  stimulates  and 
the  resultant  contraction  of  the  muscle  fibres  causes  dilatation  of  the  pupil,  but  when 
strong  impulses  descend  to  M,  as  happens  when  the  ej'c  is  exposed  to  bright  light,  the 
circular  muscle  overcomes  the  weaker  radiating  fibres,  and  the  pupil  is  contracted.  In 
the  same  way  strong  stimulation  of  M  by  muscarine  overcomes  the  stimulation  of  C  by 
cocaine,  while,  on  the  other  hand,  when  M  is  paralyzed  by  atropine  and  the  circular 
fibres  are  thus  thrown  out  of  action,  the  radiating  muscles  are  unopposed  and  cocaine 
causes  a  greater  dilatation  than  in  the  normal  eye. 


tion,  but  in  this  case  are  prevented  by  previous  section  of  the  cer\ical 
sympathetic.  Cocaine  does  not  produce  any  dilatation  of  the  pupil  in 
birds  in  which  the  iris  nniscle  is  striated. 

General  Protoplasmic  Action. — The  cH'ects  of  cocaine  on  the  nerve  fibres 
and  sensory  terminations  is  so  striking  that  its  toxic  action  on  other 
forms  of  livinjij  matter  are  lial)lc  to  be  forgotten.  The  anaesthetic  action 
is,  however,  merely  an  instance  of  its  general  toxicity,  for  if  brought 


COCAINE  357 

in  contact  with  other  forms  of  Hving  matter  in  the  concentration  used 
in  anaesthetising  nerve  ends,  it  is  i)()isonous  to  all  the  structures  which 
have  been  examined.  Even  concentrations  too  low  to  act  on  the  per- 
ipheral nerves  act  on  the  nerve  cells  and  paralyze  them,  so  that  it  is 
impossible  to  induce  a  general  loss  of  sensation  by  cocaine  injected  into 
the  circulation,  and  local  anaesthesia  can  be  induced  only  by  applying 
relatively  strong  concentrations  and  confining  their  action  to  definite 
areas.  Muscles  cease  to  contract,  the  ciliated  epithelial  cells,  leucocytes 
and  spermatozoa  become  motionless,  the  cortical  nerve  cells  lose  their 
excitability,  and  many  of  the  invertebrates  are  killed  by  even  a  short 
exposure  to  cocaine.  The  movements  of  protoplasm  in  plants  are  also 
retarded  or  entirely  suppressed  by  this  poison,  and  the  process  of  putre- 
faction is  delayed  considerably.  In  some  cases,  notably  in  the  higher 
invertebrates,  the  final  depression  is  preceded  by  a  stage  of  increased 
movements,  and  it  is  said  that  the  irritability  of  nerve  is  also  augmented 
at  first.  In  other  instances,  however,  cocaine  induces  only  depression 
and  paralysis. 

Other  examples  of  this  destructive  action  are  also  seen  in  the  thera- 
peutic use  of  cocaine,  for  the  cornea  is  often  rendered  somewhat 
cloudy  from  its  application,  and  its  subcutaneous  injection  is  some- 
times followed  by  necrosis.  Victims  of  the  cocaine  habit  often  show 
numerous  scars  on  the  arms  and  legs  from  this  local  gangrene,  although 
this  is  probably  often  due  to  unsterilized  syringes  rather  than  to  the 
solution. 

An  interesting  analogy  has  been  drawn  by  Gros  between  cocaine  and  the 
general  narcotics  of  the  alcohol-chloroform  series,  which  also  have  some  action 
on  nerve  fibres  and  terminations  when  they  are  applied  directly.  They  act 
in  lower  dilution  on  the  central  nerve  cells,  however,  and  do  not  affect  the 
sensory  fibres  more  than  the  motor,  while  the  concentration  of  cocaine  which 
affects  the  nerve  cell  is  less  distant  from  that  which  acts  on  the  peripheral 
fibre  and  it  acts  much  more  strongly  on  the  sensory  than  the  motor  nerves. 

Most  of  the  other  natural  alkaloids  resemble  cocaine  in  many  points  of 
their  action,  as  far  as  they  have  been  investigated,  but  some  of  the  artificial 
compounds  present  divergences  from  the  general  type.  Thus  a  number  of 
them  do  not  produce  anaesthesia,  and  some  of  them  depart  entirely  from  the 
typical  cocaine  action. 

Cocamine  is  often  said  to  be  a  cardiac  poison,  but  its  action  on  the  heart  seems 
to  resemble  in  general  that  of  cocaine.  It  has,  however,  a  much  more  intense 
action  on  muscular  tissue,  which  it,  like  caffeine,  throws  into  rigor  mortis. 
Its  anaesthetic  power  is  very  small.  Some  authorities  regard  the  muscular 
action  of  caffeine  as  an  important  factor  in  its  preventing  fatigue,  and  the 
presence  of  cocamine  in  the  coca  leaves  might  be  used  to  explain  the  similar 
effects  induced  by  these,  but  the  quantity  is  probably  too  small  to  have  any 
noticeable  action. 

Benzo]ilecgo7iine  is  a  comparatively  weak  body,  which  produces  symptoms 
resembling  caffeine — increased  reflex  excitability,  muscular  stiffness,  and  rigor 
— and  ecgonine  is  still  less  active,  but  elicits  similar  effects  in  frogs. 

Cocaine  Habit. — Since  the  introduction  of  cocaine  into  general  thera- 
peutic use,  numerous  cases  of  the  formation  of  a  habit  similar  to  that 
of  opium  or  morphine,  have  been  recorded.    Some  of  these  have  been 


358  SUBSTANCES  ACTING  AFTER  ABSORPTION 

due  to  the  attempt  to  substitute  eocaine  for  niorpliiue  in  the  treatment 
of  chronic  morphinism,  the  treatment  often  resulting:;  in  the  develop- 
ment of  an  irresistible  craving  for  both  alkaloids.  The  symj)toms  of 
cocainism  jienerally  begin  with  digestive  disorders,  loss  of  apjjetite, 
salivation  and  emaciation,  but  the  more  important  changes  occur  in 
the  central  nervous  system,  which  apparently  undergoes  degeneration 
similar  to  that  seen  in  chronic  morphine  poisoning.  Sleeplessness, 
tremors  and  occasionally  convulsions,  hallucinations,  insanity  and 
delirium  have  been  noted  after  long  abuse,  along  with  indefinite  dis- 
turbances of  sensation  and  motion.  The  treatment  of  these  cases  is 
the  withdrawal  of  the  drug,  and  this  can  generally  be  done  without 
the  production  of  any  special  symptoms,  though  it  is  sometimes  fol- 
lowed by  great  depression.  This  treatment  is  much  facilitated  by 
sending  the  patient  to  a  special  resort,  and,  in  fact,  is  almost  hopeless 
without  his  isolation. 

Acute  Cocaine  Poisoning  is  treated  purely  symptomatically.  Amyl- 
nitrite  has  been  advised  when  the  blood-pressure  seems  much  elevated, 
while  for  the  convulsive  attacks  small  quantities  of  chloroform  or  ether 
may  be  necessary.  Or  course,  the  stomach  ought  to  be  evacuated  first 
of  all  if  the  drug  has  been  taken  by  the  mouth. 

Preparations. 

CocAiNA  (U.  S.  P.,  B.  p.),  an  alkaloid  (C17H01NO4)  obtained  from  the  leaves 
of  Erythroxylon  coca  and  its  varieties,  forming  colorless  crystals  with  a  bitter 
taste  followed  by  numbness;   insoluble  in  water,  soluble  in  alcohol. 

Cocaine  Hydrochloridum  (U.  S.  P.,  B.  P.)  (C17H21NO4HCI),  colorless 
crystals,  very  soluble  in  water  and  alcohol;  watery  solutions  cannot  be  boiled 
as  the  alkaloid  tends  to  decompose,  0.03  G.  (|  gr.);    B.  P.,  i'„-j  gr. 

Lamellce CocainoB  (B.  P.);  each  contains  A  gr.  of  the  hydrochloride. 

Injedio  Cocaince  Hypodermica  (B.  P.),  5  per  cent.,  5-10  mins. 

The  ointment  of  cocaine  (B.  P.,  4  per  cent.)  and  the  oleate  of  cocaine  (U.  S. 
P.,  5  per  cent.),  like  the  other  cocaine  preparations  should  be  used  only  by  the 
physician,  as  they  have  repeatedly  given  rise  to  the  cocahie  habit  when  sup- 
plied to  patients.  For  this  reason  lozenges  containing  cocaine  should  not  be 
prescribed. 

The  Therapeutic  Uses  of  cocaine  are  almost  all  dependent  on  its 
anaesthetic  action.  It  has  been  suggested  as  a  brain  stimulant  in  various 
conditions  of  mental  depression,  but  has  not  been  widely  used  for  this 
purpose,  which  is  better  served  by  the  less  dangerous  caffeine.  A  wine 
containing  coca  extract  used  in  domestic  medicine  as  a  "general  tonic," 
has  repeatedly  given  rise  to  thecocaine  habit. 

Its  antesthetic  properties  rentier  it  extremely  important,  but  of  late 
years  some  of  the  artificial  substitutes  (p.  3()1)  have  been  preferred 
to  cocaine  itself  in  practice.  The  principles  of  local  aniesthesia  remain 
unchanged,  however,  and  may  be  discussed  here.  It  is  of  importance 
that  the  solutions  of  cocaine  should  be  as  dilute  as  possible,  for  much 
larger  quantities  can  be  injected  in  dilute  form  without  ri.sk  of  poisoning 
than   if  more  concentrated   solutions  are  used.     The   cocaine  hydro- 


•i 


COCAINE  359 

cliloride  should  be  dissolved  in  0.8  per  cent,  saline  solution  in  order  to 
avoid  the  effects  of  water  on  the  tissues.  In  ophthalmic  surgery  it  is 
used  very  largely  both  during  operation  and  to  alleviate  pain,  and 
occasionally  to  constrict  the  vessels  of  the  iris  in  inflammatory  condi- 
tions. For  complete  anjesthesia  a  4  per  cent.,  solution  may  be  employed, 
while  to  allay  pain  one  of  1-2  per  cent,  is  all  that  is  necessary.  The 
anesthesia  is  of  short  duration,  generally  setting  in  after  5-7  minutes 
and  passing  off  20-30  minutes  after  the  application  of  the  drug. 
Occasionally  cocaine,  especially  in  strong  solution,  produces  a  certain 
amount  of  opacity  of  the  cornea,  and  wounds  heal  less  readily,  and 
irritant  antiseptics  are  more  dangerous  with  cocaine  than  without  it. 
This  arises  from  the  general  toxic  action  of  cocaine  on  living  matter, 
which  tends  to  lessen  the  resistance  of  the  tissues  with  which  it  comes 
in  contact.  The  usual  explanation  given  that  cocaine  paralyzes  sensation 
in  the  cornea,  and  thus  prevents  the  reflex  winking  which  removes 
foreign  bodies  from  the  surface  and  keeps  the  eye  moist,  is  obviously 
insufficient,  as  the  anaesthesia  is  of  but  short  duration.  The  dilatation 
of  the  pupil  produced  by  cocaine  is  much  less  complete  than  that 
under  atropine,  and  can  only  be  taken  advantage  of  in  diagnosis  by 
using  a  very  dim  light,  as  the  pupil  contracts  in  bright  light  almost  to 
its  normal  size.  On  the  other  hand  cocaine  is  less  injurious  in  glau- 
coma and  the  dilatation  can  be  removed  at  once  by  the  instillation  of 
a  few  drops  of  physostigmine. 

In  the  nose,  throat  and  larynx,  cocaine  is  used  in  a  solution  of  4 
per  cent.,  sometimes  10-20  per  cent.,  and  anaesthesia  is  obtained  with 
greater  diflSculty  than  in  the  eye,  but  the  local  contraction  of  the  vesels 
is  often  of  great  service.  Cocaine  is  used  largely  in  operative  procedure 
here  and  also  in  the  treatment  of  irritable  conditions  of  the  respiratory 
passages,  such  as  hay  fever.  In  the  urethra,  rectum  and  vagina,  cocaine 
(1-2  per  cent.)  is  used  either  as  an  anaesthetic  or  to  relieve  pain  tempo- 
rarily. It  is  sometimes  of  service  in  painful  or  itching  skin  diseases,  but 
care  must  be  taken  not  to  apply  it  to  large  broken  surfaces,  otherwise 
symptoms  of  poisoning  may  follow.  The  local  action  on  the  stomach 
is  often  valuable  in  checking  vomiting  due  to  gastric  irritation. 

For  many  years  after  its  introduction  as  a  local  anesthetic  in  1884, 
its  use  was  practically  limited  to  minor  operations  in  the  nose  and 
throat  and  to  ophthalmic  surgery,  few  general  surgeons  venturing  on 
its  application  except  in  quite  minor  operations  which  required  only  a 
small  incision  and  no  manipulation;  for  this  purpose  cocaine  is  in 
frequent  use  in  general  practice  in  which  it  is  found  more  convenient 
than  the  local  anaesthesia  induced  by  cold  (see  p.  70).  Within  the  last 
few  years,  however,  its  use  has  undergone  a  wide  extension,  so  that 
almost  all  the  major  surgical  operations  have  been  performed  under  it, 
and  local  anesthesia  by  means  of  cocaine  or  eucaine  has  now  become 
a  rival  of  ether  and  chloroform.  Occasionally  partial  local  anesthesia 
is  combined  with  the  administration  of  small  quantities  of  chloroform 
or  ether,  which  are  insufficient  to  produce  complete  luiconsciousness, 
but  cause  a  numbing  of  the  sensatit)n,  which,  together  with  the  local 


360  SUBSTANCES  ACTING  AFTER  ABSORPTION 

action,  pennits  of  a  painless  operation.  At  first  stronjj  solutions  were 
injected  to  prepare  the  way  for  the  knife,  each  step  forward  in  the 
operation  being  preceded  by  an  injection  of  cocaine  to  induce  aiues- 
thesia  of  the  layer  of  tissue  to  be  incised.  But  this  method,  which 
has  been  used  chiefly  by  lleclus,  required  dangerous  quantities  of  the 
drug,  and  is  now  scarcely  used  except  for  minor  operations  in  which 
a  single  injection  is  sufficient.  A  more  satisfactory  method  of  local 
anjesthesia  for  operative  purposes  has  been  introduced  by  Schleich 
under  the  name  of  infiltration  ancedhesia.  A  large  quantity,  generally 
about  100  c.c.  of  a  solution  containing  0.1  per  cent,  of  cocaine  and  0.8 
per  cent,  of  sodium  chloride  is  allowed  to  permeate  the  tissues  through 
a  fine  hypodermic  needle.  Only  very  slight  pressure  is  required  and  the 
whole  of  the  surrounding  structures  become  swollen  and  oedematous 
and  can  be  cut  into  without  pain.  ]\Iuch  of  the  fluid  escapes  through 
the  incisions  and  no  symptoms  of  poisoning  arise.  Another  method 
{regional  anwslhcsia)  is  the  injection  of  cocaine  into  the  immediate 
neighborhood  of  the  nerve  supplying  the  part  to  be  operated  on..  Com- 
plete local  anaesthesia  is  obtained,  and  shock  is  less  liable  to  occur 
than  when  general  anaesthesia  is  induced  (Crile).  This  method  has  been 
used  extensively  in  operations  on  the  foot  and  hand,  for  which  it  is 
admirably  suited;  it  can  also  be  adapted  to  other  parts  of  the  body. 
The  local  action  in  both  infiltration  and  regional  anaesthesia  may  be 
augmented  and  the  danger  of  general  poisoning  lessened  b}^  retarding 
the  circulation  in  the  part  to  be  operated  on.  This  may  be  done  by 
applying  an  Esraarch  bandage  above  it  when  a  limb  is  in\'olved,  or  by 
the  application  of  cold  by  means  of  ethyl  chloride;  but  the  best  results 
are  obtained  by  using  a  1  per  mille  solution  of  adrenaline  along  with 
cocaine.  This  contracts  the  vessels  and  arrests  the  circulation  locally, 
and  the  cocaine  thus  remains  longer  unabsorbed.  Braun  recommends 
5  drops  of  1  per  mille  adrenaline  solution  to  50  c.c.  of  0.1-0.2  per  cent, 
cocaine  solution  for  infiltration. 

Another  method  of  inducing  auiesthesia  in  a  limb  is  by  means  of 
venous  injection.  The  limb  is  emptied  of  blood  by  elevation  and  bandag- 
ing and  a  tourniquet  is  applied  above  the  point  where  the  injection  is 
to  be  made;  the  cocaine  or  its  substitute  is  now  injected  under  some 
pressure  into  a  superficial  vein  peripheral  to  the  tourniquet  and  quickly 
penetrates  by  anastomosis  throughout  the  veins  of  the  limb  paralyzing 
sensation  wherever  it  reaches.  After  the  operation  the  tourniquet  is 
slowly  loosened  and  the  ana-sthesia  disai)pears  with  the  an;emia.  The 
same  strength  of  cocaine  solution  is  used  as  for  infiltration  am^-sthcsia 
and  the  quantity  is  too  small  to  have  any  efi'ect  when  it  reaches  the 
general  tissues. 

After  it  was  found  that  the  ncr\-c  impulses  from  the  periphery  to 
the  central  ner\()us  system  could  be  blocked  by  the  injection  of  cocaine 
into  the  peripheral  nerves,  the  next  step  was  to  obstruct  them  higher 
in  their  course  by  applying  it  to  the  spinal  roots  {subarachnoid  anes- 
thesia. The  first  to  attempt  this  was  (^orning  of  Xew  York,  but  the 
development  of  the  procedure  is  due  to  Bier  and  Tufiier.     A  long, 


SUBSTITUTES  FOR  COCAINE  3G1 

hollow  needle  is  passed  into  the  spinal  canal  between  the  laniinie  of 
the  lumbar  vertebne  and  1  c.c.  of  a  2  per  cent,  solution  of  cocaine 
hydrochloride  is  injecteil  after  the  withdrawal  of  an  equivalent  amount 
of  cerebrospinal  jfiuid.  The  actual  amount  of  cocaine  injected  is  thus 
0.02  G.  (I  gr.).  Within  a  few  minutes  numbness  begins,  generally 
in  the  feet  at  first,  but  sometimes  in  the  lower  part  of  the  trunk;  it 
spreads  upwards  rapidly  until  sensibility  to  pain  is  lost  everywhere 
below  the  diaphragm  and  sometimes  in  the  thorax;  in  some  cases  even 
the  head  has  been  found  amesthetized.  The  sensations  induced  by 
warmth  and  cold  are  less  quickly  affected,  touch  is  preserved  to  some 
extent  and  the  limbs  can  be  moved  readily,  though  the  movements  are 
carried  out  more  slowly  than  usual ;\he  consciousness  is  unimpaired. 
This  condition  lasts  from  half  an  hour  to  an  hour  and  then  sensation 
returns  gradually.  In  the  beginning  of  the  action  some  muscular 
twitching  is  often  seen,  and  the  muscles  are  never  relaxed  as  they  are 
under  chloroform  or  ether.  Vomiting  occurs  in  a  certain  proportion 
of  cases  either  during  or  after  the  operation,  and  persistent  headache 
is  often  present.  The  cocaine  acts  on  the  posterior  nerve  roots  and  not 
on  the  cord  itself.  The  cerebrospinal  fluid  has  been  found  to  contain 
a  large  number  of  polynuclear  leucocytes  after  the  injection  and  resumes 
its  normal  limpid  character  only  after  several  days.  This  method  of 
anaesthesia  has  been  used  in  a  large  number  of  operations,  some  of 
them  of  the  gravest  nature;  it  has  also  been  substituted  for  general 
anaesthesia  in  labor. 

Of  these  methods,  Schleich's  infiltration  has  been  most  widely 
adopted  and  is  admirably  suited  for  minor  operations.  It  is  the  safest 
method  available  for  most  of  these,  for  the  amount  of  cocaine  injected 
ought  not  to  be  sufficient  to  induce  poisonous  symptoms,  and  should 
never  exceed  20  mg.  (^  gr.),  and  much  of  this  escapes  by  the  incision. 
It  requires  some  experience  to  induce  complete  insensibility  to  pain 
by  this  method  and  the  operation  has  to  be  interrupted  at  intervals  to 
permit  of  further  injections.  Some  headache  and  nausea  are  occa- 
sional sequehe.  When  general  anaesthesia  is  contraindicated,  infil- 
tration may  be  adopted  in  major  operations,  while  on  the  other  hand 
it  is  often  contraindicated  in  minor  operations  where  there  is  any 
possibility  of  complications,  or  where  the  anxiety  and  nervousness  of 
the  patient  are  likely  to  interfere  with  the  proceedings.  Subarachnoid 
or  intraspinal  cocainization  has  been  enthusiastically  praised  by  some 
of  its  sponsors,  but  is  generally  regarded  as  a  hazardous  method.  Numer- 
ous fatalities  have  resulted  from  it,  and  headache  and  nausea  very 
often  persist  for  many  hours  after  the  operation.  It  is  less  in  use 
now  than  a  few  years  ago  and  is  only  to  be  recommended  when  special 
circumstances  contraindicate  the  general  anaesthetics,  and  operation  is 
imperative. 

Substitutes  for  Cocaine. 

In  the  early  days  of  local  anaesthesia  with  cocaine,  a  number  of 
fatalities  occurred  from  its  use  and  prompted  the  search  for  a  less 


362  SUBSTAI^CES  ACTING  AFTER  ABSORPTION 

daiiji;erous  substitute.  Witli  modern  methods  cocaine  is  much  less 
(huij^erous  and  it  has  proved  more  rehal)le  in  })ractice  than  any  of  its 
rivals.  Some  ana'sthetic  action  is  inherent  in  a  very  large  mnnber  of 
chemical  substances,  but  in  most  instances  the  amesthesia  is  preceded 
by  irritation  and  ])ain.  Even  cocaine  is  not  devoid  of  deleterious  local 
action.  In  comi)aring  the  advantages  and  drawbacks  of  the  various 
local  amesthetics,  the  points  to  be  examined  are  the  general  toxicity 
on  absorption,  the  power  of  inducing  local  anaesthesia,  and  the  extent 
to  which  the  paralysis  of  the  nerve  ends  is  preceded  by  irritation  and  is 
attended  by  injury  to  other  cells  in  the  neighborhood.  The  first  im- 
portant substitute  for  cocaine  was  Beta-Eucaine  (C15H21NO2)  which  is 
derived  from  a  base  analogous  to  cocaine,  and  like  cocaine  first  stimulates 
and  then  paralyzes  the  central  nervous  system  when  injected  into  animals 
in  large  doses;  the  pulse  is  slowed  from  direct  action  on  the  cardiac 
muscle,  and  the  blood-pressure  falls.  Eucaine  is  only  about  half  as 
poisonous  as  cocaine.  As  a  local  amesthetic,  it  is  almost  as  efficient  as 
cocaine  but  often  induces  irritation.  It  does  not  constrict  the  vessels 
nor  dilate  the  pupil;  its  effects  on  the  intraocular  pressure  are  not  yet 
satisfactorily  determined.  A  1-2  per  cent,  solution  of  the  lactate  is 
used  in  the  eye,  2-5  per  cent,  for  other  mucous  surfaces  and  for  sub- 
cutaneous injection.  Eucaine  may  be  employed  in  0.2-1  per  cent, 
solution  instead  of  cocaine  for  infiltration  anaesthesia,  and  can  be  dis- 
infected by  boiling. 

Benzamin^  Lactas  (B.  P.),  Beta-eucaine  lactate  (C15H21NO23C3H6O3), 
a  white  crystalline  powder  with  a  bitter  taste  followed  by  numbness, 
soluble  in  5  parts  of  water.     Dose,  |-|  gr. 

Tropacocaine,  an  alkaloid  found  in  Java  coca  leaves,  is  the  benzoic 
ester  of  a  base,  pseudotropine.  It  is  about  half  as  poisonous  as  cocaine 
when  absorbed.  Applied  locally  it  equals  cocaine  in  anaesthetic  power, 
but  its  effects  are  more  transient  and  it  is  more  liable  to  cause  irritation 
according  to  some  observers.  It  has  not  been  employed  so  widel}'  as 
the  others.    Applied  to  the  eye  it  does  not  dilate  the  pupil. 

Stovaine,  Ci4H2i02N,HCl,  an  artificial  alkaloid  recently  introduced,  is 
less  poisonous  than  cocaine,  but  has  occasionally  caused  alarming 
symptoms  of  collapse.  Its  local  ana?sthetic  action  is  comi)arable  to 
that  of  cocaine,  but  is  attended  by  some  signs  of  irritant  action. 

Alypine,  Ci6ll2602N2,HCl,  is  closely  related  to  stovaine  in  chemical 
structure.  It  is  equally  poisonous  with  cocaine  and  though  it  also 
equals  it  in  its  local  anaesthetic  action,  this  is  attended  by  marked 
irritant  congestion  and  even  sloughing.  Alypine  has  therefore  no 
claims  to  use  in  therapeutics. 

Novocaine  (NH2 — C6H4 — COC2H4N (€2115)2)  is  about  one-third  as 
poisonous  as  cocaine,  and  applied  locally  acts  only  on  the  nerves  with- 
out involving  the  other  tissues  and  thus  produces  no  irritation  or  hyper- 
lemia;  it  does  not  constrict  the  vessels  as  cocaine  does.  Its  ana'sthetic 
action  is  less  powerful  and  less  lasting  than  that  of  cocaine,  but  is 
sufficient  for  most  i)urp()ses  when  the  absorption  is  delayed  by  the 
addition  of  adrenaline. 


SUBSTITUTES  FOR  COCAINE 


363 


Nirvanine,  C14H20O4N2HCI,  is  less  poisonous  than  cocaine  and  is  also 
less  aua'sthetic  and  has  not.  been  used  to  the  same  extent  as  the  others. 
Its  two  allies,  Subcutine  and  Anaesthesin,  have  also  been  used  too  little 
to  allow  of  a  definite  statement  of  their  merits." 

Orthoform  and  Orthoform-neu,  are  esters  of  amino-oxybenzoic  acid, 
and  are  almost  insoluble  in  water.  They  have  been  used  as  dusting 
powders  and  in  ointment  to  allay  pain  in  ulcers  and  burns;  but  in  a 
number  of  instances  they  have  given  rise  to  severe  irritation  and  slough- 
ing, and  they  must  be  used  with  the  greatest  care,  if  at  all.  Orthoform 
has  no  action  on  the  unbroken  skin  and  its  insolubility  precludes  its  use 
as  a  substitute  for  cocaine  by  hypodermic  injection. 

Holocaine  is  a  phenetidine  derivative,  Ci8H2202N2,  which  has  been 
used  to  some  extent  and  is  said  to  be  less  poisonous  than  cocaine  and 
nearly  twice  as  powerful  in  its  anaesthetic  action. 

A  comparison  of  the  relative  anaesthetic  action,  irritant  action,  and 
toxicity  of  these  bodies  determined  in  animals  is  given  in  the  following 
table : 


Anaesthetic 

Irritant 

Toxicity. 

action. 

action. 

Cocaine 

1 

1 

+ 

Eucaine 

0.4 

1 

+  + 

Tropacocaine  . 

0.5 

1 

+  + 

Stovaine     . 

0.6 

1 

+  + 

Alypine 

0.9-1.25 

1 

+  +  +  + 

Novocaine  . 

0.3-0.5 

0.1 

Absent 

Nirvanine  . 

0.3-0.7 

0.4 

+  + 

Holocaine  . 

0.6 

2.0 

+ 

According  to  Gros,  all  of  these  drugs  have  the  same  anjesthetic  power 
if  they  are  applied  as  bases,  and  if  this  proves  to  be  correct,  no^-ocaine 
has  great  advantages  over  the  others  if  used  in  solutions  containing 
sodium  bicarbonate  in  sufficient  amount  to  free  the  alkaloid  in  basic 
form. 

In  practice  cocaine,  eucaine,  and  stovaine  are  in  common  use.  Novo- 
caine is  less  powerful  but  less  irritant  and  is  gaining  in  popularity.  Holo- 
caine and  tropacocaine  deserve  more  attention  than  they  have  received 
as  yet. 

Yohimbine. 

Yohimbine  is  an  alkaloid  (C23H32N2O4)  obtained  from  the  bark  of  the  Yohim- 
behe  tree  (Corynanthe  yohimbi)  and  resembles  cocaine  in  some  of  its  effects. 
Thus,  it  has  the  same  ana-sthetic  action  on  sensory  nerve  terminations  and 
on  nerve  trunks,  and  in  poisonous  doses  induces  somewhat  similar  symptoms  of 
stimulation  of  the  central  nervous  system.  It  appears  to  increase  the  activity 
of  the  respiratory  centre  in  particular,  for  even  small  quantities  accelerate  and 
deepen  the  respiration.  The  heart  is  hardly  affected  except  in  toxic  doses,  but 
quantities  which  induce  no  other  symptoms  except  from  the  respiration,  dilate 
the  vessels  of  the  skin  and  of  the  genital  organs  from  a  direct  action  on  the 
vessel  walls.  The  last  become  turgid  and  congested  from  the  dilation  of  the 
arterioles  and  erection  follows.  Miiller  states  that  the  genital  reflexes  are  also 
rendered  more  acute  and  that  all  the  symptoms  of  sexual  excitement  are  ob- 
served  both   in  male  and  female  animals.     Yohimbine  chloride  and  lactate 


364  SUBSTANCES  ACTING  AFTER  ABSORPTION 

have  been  used  in  veterinary  medicine  and  also  in  man  to  induce  erection  and 
impro\'e  sexual  power  in  cases  of  neurasthenic  impotency  and  similar  con- 
ditions.    Dose,  5  mgs.  (,',  gr.). 

Bibliography. 

V.  Anrep.     Pfliiger's  Archiv,  xxi,  p.  38,  1880. 

Mosso.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxiii,  p.  1.5.3.     Pfliigor's  Arohiv,  xlvii,  p.  .'553. 
Alms.     Arch.  f.  Anat.  u.  Phys.,  1886.     Supplement,  p.  29.3. 
Kiesow.     Wiindt'.s  Philosoph.  Studien,  ix,  p.  510. 
Stockman.     Brit.  Med.  Journal,  1889,  i,  p.  1043. 
Poulsson.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxvii,  p.  301. 
Limbourg.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxx,  p.  93. 
Rcichert.     Philadelphia  Med.  Journ.,  1902. 

Marcinowski.     Deutsch.  Ztschr.  f.  Chir.,  Ixv,  p.  417.      (Eucaine.) 
Cliadbourne.     Brit.  Med.  Journ.,  1892,  ii,  p.  402.     (Tropacocaine.) 

Vinci.     Virchow's  Arch.,  cxlv,  p.  78.     (Eucaine.)     Arch.  f.  Anat.  u.  Phys.,   1897,  p. 
163.     Virchow's  Arch.,  cxlix,  p.  217;    cliv,  p.  549. 

Einhorn  u.  Heinz.     Miinch.  med.  Woch.,  1897,  p.  931.     (Orthoform.) 

Soulier  el  Guinard.     Arch,  internat.  de  Pharmacodyn.,  vi,  p.  1. 

Dixon.     Journ.  of  Physiol.,  xxxii,  p.  87. 

Braun.     Arch.  f.  kUn.  Chir.,  Ivii,  p.  370;   Ixix,  p.  541. 

Bier.     Ibid.,  Ixiv,  p.  236. 

Mailer.     Arch,  internat.  de  Pharmacodyn.,  xvii,  p.  81.     (Yohimbine.) 

Gunn.     Ibid.,  xviii,  p.  95;   Quart.  Journ.  of  Exp.  Physiol.,  i,  p.  191.     (Yohimbine.) 

Grode.     Arch.  f.  exp.  Path.  u.  Pharm.,  Ixvii,  p.  172. 

Rifatwaclidani.     Biochem  Zeitschr.,  liv,  p.  83. 

Gros.     Arch.  f.  exp.  Path.,  Ixii,  p.  380;    Ixiii,  p.  80;    Ixiv,  p.  67;    Ixvii,  pp.  126,  132. 

Le  Brocq.     Brit.  Med.  Journ.,  March  27,  1909. 

Braun.     Die  Lokalanaesthesie.    Leipsig,  1905. 


XV.    ADRENALINE. 

The  suprarenal  glands  of  all  vertebrates  have  been  shown  to  contain 
a  body  which  possesses  a  pow^erful  action  on  the  organism,  and  which 
the  glands  normally  secrete  into  the  bloodvessels.  The  active  prin- 
cii)le  was  first  isolated  by  Abel  and  named  epinephrine,  but  is  more 
widely  known  under  the  trade  names  of  adrenaline,  suprarenine,  etc. 
It  has  also  been  found  by  Abel  in  the  external  neck  glands  of  a  tropical 
toad.  It  is  a  feebly  basic  derivative  of  benzene,  corresponding  to  the 
formula  CbH,3(()H)2— CHOII— Clio— NHCH3.  Adrenaline  has  been 
formed  synthetically,  and  a  number  of  other  amine  compounds  similar 
to  it  in  structure  have  proved  to  resemble  it  also  in  action  in  many 
features;  other  amines  less  closely  related  chemically  tend  to  depart 
further  from  the  typical  adrenaline  action  (Barger  and  Dale).  Adrena- 
line is  lanorotary  to  polarized  light;  the  dextrorotary  isomer  has  only 
about  one-twelfth  of  the  activity  of  the  natural  substance  (cf.  Atropine 
and  Hyoscine). 

The  characteristic  action  of  adrenaline  is  best  elicited  by  its  injec- 
tion into  a  vein,  when  it  stimulates  the  myoneural  junctions  of  the 
postganglionic  fibres  of  the  symi)athctic  nerves.  The  effects  of  adrena- 
line are  thus  for  the  most  part  identical  with  those  of  stimulation  of  the 
sympathetic  nerves  and  the  group  of  amines  of  which  it  is  the  best 
known  member  have  therefore  been  termed  the  sympatho-mimetic 
amines.      The  symi)toms  siiow  certain  analogies  with  those  imluced 


ADRENALINE  365 

by  nicotine,  but  the  latter  affects  a  wider  area  from  its  involving  the 
cranial  and  pelvic  autonomic  nerves  as  well  as  those  of  the  true  sym- 
pathetic. And  the  point  at  which  nicotine  acts  is  the  ganglion  cell, 
while  adrenaline  involves  the  other  end  of  the  peripheral  neuron.  It 
should  be  added  that  some  of  the  sympathetic  terminations  are  not 
involved  in  the  action  of  adrenaline;  the  secretory  fibres  in  the  sweat 
glands  are  not  affected  for  example,  although  they  are  of  sympathetic 
origin. 

Circulation. — On  the  intravenous  injection  of  adrenaline  a  very 
marked  rise  in  the  arterial  blood-pressure  occurs  accompanied  at  first 
by  acceleration,  then  by  slowing,  and  later  again  by  acceleration  of  the 
heart.  This  rise  in  blood-pressure  is  for  the  most  part  due  to  constriction 
of  the  vessels  of  the  abdominal  cavity,  but  an  increase  in  the  efficiency 
of  the  heart  often  plays  a  part,  though  a  subordinate  one.  The  sudden 
increase  in  pressure  occurs  after  destruction  of  the  vasomotor  centre 
and  cord,  or  after  section  of  the  splanchnic  nerves  and  paralysis  of  the 
ganglia  on  the  vaso-constrictor  nerves,  so  that  it  is  obviously  due  to 
direct  action  on  the  muscle  of  the  vessel  walls,  or  on  the  terminations 
of  the  nerves  in  them.  The  greatest  constriction  is  seen  in  the  vessels 
of  the  splanchnic  area,  but  most  of  the  other  vessels  are  also  involved 
in  lesser  degree.  Thus  the  limb  vessels  are  narrowed  less  than  those 
of  the  intestine,  and  the  pulmonary  and  cranial  arterioles  are  so  slightly 
constricted  that  there  has  been  some  difficulty  in  proving  that  they 
are  involved  in  the  general  action;  most  observers  now  hold  that  there 
is  narrowing  in  these  regions  also.  The  effect  on  the  coronary  artery 
of  the  heart  has  also  been  the  subject  of  dispute,  most  investigators 
finding  that  it  is  dilated  by  adrenaline;  but  though  this  is  often  the 
prevailing  effect,  very  small  concentrations  of  adrenaline  cause  distinct 
contraction  of  the  coronary  artery  and  slow  the  passage  of  blood  through 
the  heart  (Brodie  and  Cullis).  Even  in  organs  in  which  the  vessels  are 
more  obviously  constricted,  the  degree  varies  considerably,  apparently 
according  to  the  amount  of  control  normally  exercised  by  the  constrictor 
nerves;  thus  the  vessels  of  the  uterus  are  more  contracted  than  those  of 
the  bladder,  and  these  again  more  than  those  of  the  striated  muscles. 

After  moderate  quantities  of  adrenaline  the  blood-pressure  falls 
again  after  about  five  minutes,  and  not  infrequently  descends  below 
tile  normal  level.  And  in  some  instances  when  adrenaline  is  injected 
into  an  animal  whose  blood-pressure  is  very  high,  a  fall  of  pressure 
occurs  instead  of  the  usual  rise.  This  is  due  to  the  fact  that  adrenaline 
affects  not  only  the  vasoconstrictor  mechanism,  but  also  the  vasodilator, 
and  the  stimulation  of  the  latter  dilates  the  vessels  and  reduces  the 
blood-pressure;  as  a  general  rule,  however,  the  constrictor  nerves  are 
so  much  more  powerful  than  the  dilator  that  the  simultaneous  stimula- 
tion of  the  latter  fails  to  appear;  it  ma>'  be  demonstrated  by  the  use 
of  ergotoxine  which  paralyzes  the  constrictor  myoneural  junction  while 
leaving  the  dilator  unaffected,  so  that  after  ergotoxine  the  injection  of 
adrenaline  invariably  causes  a  fall  of  blood-pressure. 

The  acceleration  of  the  heart  under  adrenaline  is  due  to  stimulation 


366  SUBSTANCES  ACTING  AFTER  ABSORPTION 

of  the  terminations  of  the  accelerator  nerves  in  the  heart-muscle,  and 
is  therefore  accompanied  by  a  stronger  contraction  and  more  complete 
evacuation  of  the  chambers;  if  the  dose  injected  be  large  the  accelerator 
action  is  too  great  to  admit  of  complete  relaxation  during  the  diastole, 
and  the  output  of  the  heart  may  be  smaller,  and  a  drop  in  the  blood- 
pressure  is  observed.  This  accelerated  beat  is  the  characteristic  feature 
of  the  adrenaline  action,  but  it  often  giv^es  place  to  the  slow,  full  beat 
characteristic  of  inhil)itory  activity.  This  second  phase  of  slowing  of 
the  heart  beat  is  not  obser\'ed  if  the  vagi  are  di\'ided  or  if  atropine  is 
given  before  adrenaline,  so  that  it  obviously  arises  from  excitation  of 
the  vagus  centre;  this  excitation  is  not  a  direct  adrenaline  action  but 
is  a  secondary  result  of  the  high  l)lood-pressure,  which  induces  congestion 
of  the  brain  and  arouses  the  vagus  centre  to  activity.  After  a  short 
time,  the  blood-pressure  beginning  to  fall  or  the  vagus  centre  becoming 
exhausted,  the  accelerator  stimulation  again  gains  the  upper  hand  and 
the  pulse  is  again  much  accelerated. 

Fig.  .34 


Blood-pressure  (B.P.)  and  bowel  volume  (I.V.)  of  cat.  At  -4  injection  of  adrenaline. 
The  blood-pressure  rises  and  bowel  volume  diminishes,  indicating  constriction  of  the 
mesenteric  vessels.  As  these  relax  again  the  blood-pressure  falls.  The  vagi  had  been 
divided  previously,  so  that  there  is  no  secondary  slowing  of  the  heart. 

The  effect  of  adrenaline  on  the  mammalian  heart  is  thus  in  small 
dose  to  accelerate  and  strengthen  it;  in  large  amounts  the  acceleration 
may  be  excessive  and  impair  its  efficiency,  or  the  acceleration  may  be 
temporarily  replaced  by  inhibition  which  also  reduces  the  output. 
Adrenaline  increases. the  irritability  of  the  heart  and  thus  j)redisposes 
it  to  pass  into  fibrillary  contractions.  The  frog's  heart  is  less  easily 
affected  than  that  of  tiie  mannnals,  but  similar  changes  have  been 
observccl. 

The  action  on  the  heart  may  lu'  dcinoiistratcd  by  jx-rfusing  \"cr\' 
dilute  solutions  of  adrenaline  through  the  vessels  of  the  excised  heart, 
and  the  same  method  is  used  in  investigating  its  action  on  the  ves.'^els 
of  other  organs.     In  the  excised  heart  the  accelerator  and  augmentor 


ADRENALINE 


367 


action  alone  is  visible,  the  stage  of  slowing  being  absent.  The  con- 
traction of  the  vessels  in  such  organs  as  the  kidney  is  shown  by  the 
diminished  outflow  from  the  veins  when  adrenaline  is  added  to  the 
perfusing  fluid;  and  different  organs  respond  in  different  degrees,  little 
retardation  of  the  flow  occurring  in  the  lungs,  brain  and  heart  com- 
pared with  that  in  the  intestines,  limbs,  and  kidney.  A  similar  con- 
striction of  the  vessels  may  be  observed  when  a  solution  of  adrenaline  is 
applied  to  a  mucous  membrane,  for  the  part  becomes  pale  and  anaemic 
from  the  constriction  of  the  vessels;  this  is  w^ell  seen  when  the  drug 
is  applied  to  the  congested  conjunctiva  or  to  the  mesentery.  Painted 
on  the  unbroken  skin  adrenaline  has  no  effect,  as  it  fails  to  penetrate 
it,  but  denuded  surfaces  become  blanched,  and  haemorrhage  ceases 
from  small  vessels. 

Fig.  35 


Tracing  of  the  movements  of  intestine  (/)  and  of  the  uterus  (C/)  of  a  rabbit  under 
adrenaline  injected  at  the  point  marked  with  an  arrow.  The  intestine  relaxes,  while  the 
uterus  contracts  powerfully. 


When  it  is  injected  hypodermically,  the  skin  and  subcutaneous  tissues 
around  the  point  of  injection  become  pale  and  anaemic  and  may  be  cut 
into  without  bleeding,  and  when  it  is  applied  to  a  bleeding  surface,  the 
luiemorrhage  is  arrested  unless  some  large  artery  has  been  opened.  But 
even  the  direct  application  of  adrenaline  to  a  lesion  of  the  lung  or 
brain  has  little  effect  in  stopping  the  bleeding,  the  vessels  in  these 
organs  not  being  constricted  by  adrenaline  to  the  same  extent  as  those 
of  other  organs. 

Stomach  and  Intestine. — The  intravenous  injection  of  adrenaline  is 
followed  by  immediate  cessation  of  the  movements  of  the  stomach  and 
intestine  which  become  relaxed  to  their  full  extent.  This  is  in  accord- 
ance with  their  innervation,  for  the  splanchnic  fibres  are  the  inhibitory 
nerves  of  those  organs  and  their  stimulation  also  arrests  peristalsis 
and  causes  relaxation  (Fig.  35).     But  certain  specialized  parts  of  the 


368  SUBSTANCES  ACTIXG  AFTER  ABSORPTIOX 

bowel  wall  receive  motor  fibres  from  the  sympathetic — the  pyloric, 
ileo-colic  and  internal  anal  sphincters — and  these  are  thrown  into 
contraction  by  adrenaline.  The  movements  of  the  gall-bladder  are 
inhibited,  and  those  of  the  gall-dnct  are  increased  by  sympathetic 
stimulation  and  also  by  adrenaline. 

The  reaction  of  the  Bladder  to  adrenaline  differs  in  different  species 
of  animals  according  to  the  nature  of  the  dominant  impulses  of  the 
lumbar  sympathetic  nerves. 

Uterus. — The  reaction  of  the  uterus  to  adrenaline  differs  in  different 
animals  and  even  in  the  same  animal  at  different  periods.  In  the 
non-pregnant  cat,  adrenaline  generally  causes  inhibition  of  the  move- 
ments and  relaxation,  while  in  the  pregnant  cat  its  injection  is  followed 
by  powerful  contractions;  in  the  rabbit  adrenaline  almost  always  causes 
contraction  whether  the  animal  is  gravid  or  not,  while  in  the  dog  the 
uterus  first  contracts  and  then  passes  into  a  position  of  relaxation  and 
inhibition.  In  each  case  the  action  of  adrenaline  is  identical  with  that 
of  stimulation  of  the  hypogastric  nerves  which  carry  both  motor  and 
inhibitory  fibres  to  the  uterus;  the  relative  power  of  the  two  sets  of 
fibres  varies  in  different  animals  and  in  different  conditions  in  the  same 
way  as  the  action  of  adrenaline  (Fig.  35). 

The  Eye. — The  intravenous  injection  of  adrenaline  is  followed  by 
dilatation  of  the  pupil,  the  eyelids  are  widely  opened,  the  eyeball  is 
protruded,  and  the  nictitating  membrane  withdrawn;  the  action 
corresponds  exactly  to  the  effects  of  stimulation  of  the  cervical  sympa- 
thetic fibres;  it  occurs  when  these  have  been  cut,  and  is  even  intensified 
when  they  have  been  allowed  to  degenerate.  Applied  locally  to  the  eye, 
it  constricts  the  vessels  of  the  conjunctiva  and  often  dilates  the  pupil 
and  reduces  the  intra-ocular  tension  for  a  short  time. 

Bronchial  Muscle. — Adrenaline  injected  intravenously  dilates  the 
bronchi  widely,  an  effect  which  is  especially  noticeable  when  they  have 
been  previously  constricted  by  pilocarpine  or  physostigmine.  This  is 
not  the  same  as  the  dilation  caused  by  atropine,  but  arises  from  adrena- 
line stimulating  the  terminations  of  the  bronchial  sympathetic  fibres, 
which  cause  relaxation  of  the  muscle. 

Other  Organs  containing  unstriated  muscle  are  similarly  affected, 
some  undergoing  contraction,  while  others  are  inhibited  under  adrenaline, 
and  in  each  case  the  result  corresponds  with  the  effect  of  stinndation 
of  the  fibres  of  the  sympathetic  supply. 

The  Secretions  do  not  present  such  marked  changes  under  adrena- 
line, though  they  are  also  generally  increased  when  they  are  controlled 
})y  the  symi)atlietic  nerves.  This  is  due  to  the  fact  that  the  blood 
supply  is  simultaneously  reduced  by  the  vaso-constriction,  for  Edmunds 
has  shown  that  the  secretion  of  the  pancreas  is  arrested  by  adrenaline 
causing  ischannia  of  the  gland.  The  saliva  under  adrenaline  corre- 
sponds in  character  with  that  secreted  on  stinuilation  of  the  cervical 
sympathetic  trunk,  not  witli  that  from  stinuilation  of  the  chorda 
tymj)ani,  wliicli  is  a  cranial  autonomic  nerve  and  is  therefore  not  sus- 
cei)til)Ic   to  adrenaline.     The  .sii-raf  glands  provide  the  most  notable 


ADRENALINE  369 

exception  to  the  rule  that  adrenaline  has  the  same  effect  as  sympathetic 
stimulation,  for  though  they  are  innervated  by  sympathetic  fibres 
whose  stimulation  causes  secretion,  adrenaline  has  no  effect  on  the  sweat 
secretion,  whether  it  is  injected  intravenously  or  applied  locally.  The 
nerves  to  the  sweat  glands  are  anomalous  in  another  feature  for  their 
terminations  are  the  only  example  in  which  atropine  parah'zes  sympa- 
thetic terminations. 

The  secretion  of  the  urine  is  often  arrested  immediately  on  the 
injection  of  adrenaline  and  is  then  considerably  augmented.  This 
appears  to  be  due  to  the  vascular  action,  the  renal  vessels  being  con- 
stricted at  first  but  relaxing  sooner  than  those  of  the  other  organs; 
the  flow  of  blood  through  the  kidne\'  is  thus  reduced  at  first  and  the 
urinary  secretion  falls  or  stops  altogether;  then  an  abnormally  large 
flow  occurs  from  the  renal  vessels  dilating  while  the  blood-pressure  is 
still  high,  and  more  urine  is  secreted  accordingly. 

There  is  some  reason  to  believe  that  the  injection  of  adrenaline  may 
stimulate  the  suprarenal  glands  to  secretion  through  acting  on  the 
sympathetic  terminations  in  the  glands,  but  this  has  not  been  con- 
clusively established. 

The  glycogenic  function  of  the  liver  is  disturbed  by  the  presence  of 
excess  of  adrenaline  and  the  result  is  an  unusual  hydrolysis  of  glycogen 
and  an  unusual  amount  of  sugar  in  the  blood  and  tissues,  which  may 
give  rise  to  glycosuria.  This  is  not  generally  seen  when  a  single  intra- 
venous injection  is  made,  apparently  because  the  action  is  too  short; 
but  it  may  be  induced  by  the  prolonged  intravenous  infusion  of  dilute 
adrenaline  solutions,  and  very  frequently  arises  from  the  subcutaneous 
injection  of  large  amounts.  This  accelerated  breaking  down  of  glycogen 
appears  to  arise  from  adrenaline  stimulating  the  terminal  mechanism 
of  the  sympathetic  nerves  in  the  liver  that  control  the  glycogenic  func- 
tion. The  action  is  thus  of  the  same  character  as  that  in  other  organs 
and  perhaps  differs  only  in  being  slower  and  thus  requiring  a  longer 
period  of  action  than  is  necessary  to  induce  obvious  changes  in  the 
bloodvessels  and  unstriated  muscle.  The  statement  is  sometimes  made 
that  the  glycosuria  does  not  occur  after  adrenaline  in  animals  in  which 
the  thyroid  glands  have  been  excised  previously,  but  this  is  not  generally 
correct;  the  glycosuria  is  not  a  constant  feature  after  adrenaline  e\'en 
in  normal  animals,  and  inferences  from  its  absence  ought  to  be  drawn 
only  with  the  greatest  reserve. 

Adrenaline  thus  acts  in  the  same  way  as  stimulation  of  the  sympa- 
thetic nerves  and  is  held  to  induce  its  effects  by  stimulating  the  mechan- 
ism lying  between  the  nerves  and  the  muscle.  It  obviously  does  not 
act  on  the  contractile  muscle  itself,  for  some  involuntary  muscle  con- 
tracts under  it  while  in  other  organs  it  relaxes.  And  it  is  found  that 
under  ergotoxine,  an  alkaloid  which  antagonizes  the  action  of  adrenaline 
in  some  organs,  the  muscle  remains  active  though  the  receptor  on  which 
adrenaline  acts  is  paralyzed.  Adrenaline  therefore  does  not  act  on  the 
contractile  mechanism  of  muscle.  On  the  other  hand  it  does  not  act 
on  the  anatomical  nerve  ends,  for  after  these  have  degenerated  and 
24 


370  SUBSTANCES  ACTING  AFTER  ABSORPTION 

disappeared,  the  usual  effects  of  adrenaline  are  elicited  by  its  injection. 
It  is  obvious  that  the  action  is  exercised  on  some  substance  intermediate 
between  the  nerve  and  the  contractile  material  of  muscle  and  this 
has  been  termed  the  "myoneural  junction." 

Adrenaline  injected  intravenously  acts  in  very  small  quantities, 
^^U)n  nig-  often  sufficinjj  to  raise  the  blood-pressure  in  the  dog.  The 
effect  is  of  very  short  duration,  but  it  may  be  repeated  indefinitely  by 
fresh  injections,  and  this  is  generally  agreed  to  be  due  to  the  rapid 
destruction  of  adrenaline  in  the  tissues.  Elliott  states  that  this  destruc- 
tion takes  place  more  rapidly  in  those  organs  in  which  adrenaline  acts 
strongly  than  in  others,  and  it  certainly  is  not  destroyed  in  the  blood- 
plasma.  When  the  blood-pressure  regains  its  normal  level  after  an 
injection  of  adrenaline,  none  of  the  alkaloid  can  be  detected  in  the 
blood  or  tissues,  the  whole  having  undergone  oxidation.  Straub  classes 
adrenalin  among  the  "potential"  poisons  and  holds  that  it  acts  only 
in  the  process  of  permeation  into  the  cells  which  are  affected  by  it; 
when  it  has  reached  the  interior  it  is  at  once  destroyed  and  the  action, 
therefore,  lasts  only  as  long  as  there  is  adrenaline  in  the  blood  in  excess. 
A  new  injection  by  increasing  the  concentration  in  the  blood  causes 
further  permeation  into  the  cell  and  renews  the  action. 

Adrenaline  applied  locally  induces  such  vaso-constriction  that  it  is 
only  slowly  absorbed;  and  it,  therefore,  has  only  local  effects  when 
it  is  given  by  the  mouth.  Injected  hypodermically  it  causes  local 
ischjemia,  but  no  further  effects  except  in  enormous  doses.  In  par- 
ticular the  blood-pressure  is  seldom  increased  by  this  method  of 
administration;  injected  intramuscularly  it  seems  to  have  rather  more 
general  effect  and  the  blood-pressure  often  rises,  though  not  invarial)ly. 

Animals  are  poisoned  by  large  amounts  injected  hypodermically, 
and  even  smaller  quantities  induce  glycosuria  and  diuresis.  Larger 
(piantities  cause  prostration,  collapse  and  paralysis  of  the  central  nervous 
system,  ending  in  failure  of  the  respiration  and  oedema  of  the  lungs. 
Similar  symptoms  arise  from  the  intravenous  injection  of  very  large 
quantities,  but  here  the  effects  of  the  very  high  blood-pressure  are  also 
in  evidence  in  numerous  hicmorrhages.  The  intravenous  injection  of 
adrenaline  in  the  rabbit  often  leads  to  atheromatous  degeneration  of  the 
aorta,  apparently  from  the  strain  caused  by  the  high  arterial  pressure; 
it  does  not  occur  in  other  animals. 

Preparations. — Extracts  were  at  first  made  from  the  fresh  glands, 
but  soon  the  dried  glands  were  introduced — (jlandul(F  suprarcnales 
nU'ccb  {V .  S.  P.),  the  dried  glands  of  the  sheep  or  ox — and  a  watery 
solution  made  from  these  may  be  used.  The  active  principle  has  been 
put  on  the  market  under  the  name  of  adrp:naline,^  and  this  has 
almost  entirely  suj^planted  the  cruder  i)reparations. 

Adhknaliniim  (B.  p.),  CJIi.fXO;!,  a  light  brown  or  nearly  white 
powder  very  slightly  soluble  in  water;  it  may  be  obtained  from  the 
suprarenal  glands  of  animals  or  may  i)e  formed  synthetically. 

'  Other  immcs  applied  to  this  .substatuH?  jirn  adrcninc,  suijrarciialiiic,  vasoconstrictiiic, 
adncphriiic,  supracapsulino,  hcniostasiiie,  hcmisine. 


ADRENALINE  371 

Liquor  Adrenalini  Hydrociiloricus  (B.  P.),  a  one  per  lOOf)  solu- 
tion with  sodium  chloride  (0.9  per  cent.),  chloroform,  and  hydrochloric 
acid.     Dose,  10-30  mins. 

Synthetic  adrenaline  has  been  introduced  under  the  name  siiivarcnine 
and  has  the  same  action  as  the  natural  base.  Several  other  nearly 
related  sul)stances,  such  as  epinine  (C6H3(OH)2.CH2.CH2NHCH3),  have 
effects  similar  to  adrenaline,  but  none  of  them  are  so  active. 

Therapeutic  Uses. — Disease  of  the  suprarenal  gland  leads  to  a  series 
of  symptoms  known  as  Addison's  disease,  and  it  was  hoped  that  the 
extract  of  the  gland  might  counteract  this  condition  by  supplying 
the  substance  whose  deficiency  induced  the  symptoms.  i\.s  a  matter 
of  fact,  however,  no  success  has  attended  its  use  for  this  purpose,  and 
the  failure  may  perhaps  be  due  to  the  method  of  application,  for  it  has 
been  shown  repeatedly  that  the  characteristic  effects  of  adrenaline 
cannot  be  elicited  by  its  administration  by  the  mouth  or  subcutaneously. 
It  is  possible  that  adrenaline  might  prove  beneficial  if  it  could  be 
brought  into  the  blood  directly,  but  this  is  quite  impossible  in  a  chronic 
condition  such  as  Addison's  disease. 

Its  general  action  on  the  circulation  may  be  induced  in  such  emer- 
gencies as  heart  failure  or  shock,  in  which  its  powers  of  restoring  the 
circulation  have  been  proved  both  in  animals  and  in  man;  it  is  to  be 
borne  in  mind  that  adrenaline  may  tend  to  cause  fibrillation  of  the 
ventricle.  In  order  to  elicit  this  action,  the  drug  must  be  injected 
intravenously.  Given  by  the  mouth  it  has  no  effect  on  the  blood- 
pressure  or  heart;  y^iy-^V  gr-  injected  hypodermically  may  some- 
times increase  the  blood-pressure  and  strengthen  the  heart,  but  has 
generally  no  effect  except  the  local  ischaemia;  when  injected  intra- 
muscularly, this  amount  often  induces  a  marked  rise  in  pressure,  begin- 
ning in  about  four  minutes  and  lasting  15-45  minutes.  In  inaccessible 
haemorrhage,  its  intravenous  injection  might  conceivably  constrict  the 
vessels  and  permit  of  the  formation  of  a  clot,  but  the  great  rise  of 
pressure  would  tend  to  increase  the  haemorrhage,  and  its  use  is  therefore 
hazardous  and  has  generally  been  found  inefficacious. 

The  great  use  of  suprarenal  preparations  is,  however,  due  to  its 
local  effects  on  the  vessels.  No  other  body  is  known  which  induces 
such  complete  contraction  of  the  vessels  in  any  part  to  which  it  is 
applied,  and  in  addition  suprarenal  extract  has  only  local  effects,  unless 
it  is  injected  into  the  blood.  Complete  bloodlessness  of  a  part  may 
thus  be  elicited  without  alteration  of  the  general  blood-pressure,  and 
in  fact  without  any  appreciable  effect  upon  other  parts  of  the  body. 
This  local  ischaemia  has  been  largely  employed  to  allow  of  bloodless 
operations  on  the  eye  and  to  remove  congestion  of  the  conjunctiva 
from  various  causes.  It  is  often  administered  with  cocaine  in  opera- 
tions on  the  eye  (1  of  adrenaline  solution  in  10).  In  congestion 
of  the  nasal  mucous  membrane  and  in  operations  on  the  nose  it  is 
also  used  extensively  and  with  much  success;  the  1  per  mille  solution 
may  be  sprayed  into  the  nose,  or  cotton  soaked  in  it  may  be  packed 
into  the  cavit>'.      In  epistaxis  and  in  operations  on  the  nose,  the  haem- 


372  SUBSTANCES  ACTING  AFTER  ABSORPTION 

orrhage  cccases  almost  completely  and  the  contraction  of  the  mucous 
membrane  permits  of  a  clearer  view  of  the  field  of  operation.  Hay 
fever  is  often  relieved  by  similar  treatment  with  suprarenal  prepara- 
tions. A  solution  of  adrenaline  has  been  found  useful  in  hiemor- 
rhage  from  the  ear,  mouth,  and  throat,  and  in  controlling  haemorrhage 
in  operations  in  general  surgery. 

Griinbaum  first  suggested  its  administration  by  the  mouth  in  gastric 
hjemorrhage,  in  which  the  action  is  confined  to  the  mucous  membrane 
of  the  stomach.  Similarly  it  may  be  injected  into  the  rectum,  bladder 
and  uterus  in  congestion  or  haemorrhage  from  these  organs,  and  Schafer 
recommends  it  especially  in  post-partum  haemorrhage,  in  which  it  acts 
not  only  on  the  uterine  vessels  but  also  on  the  muscular  walls,  and 
arrests  the  bleeding  by  causing  a  tonic  contraction.  In  all  of  these 
cases  the  adrenaline  has  to  be  applied  directly  to  the  bleeding  organ. 
The  local  contraction  of  the  vessels  lasts  very  much  longer  than  that 
induced  by  intravenous  injection,  for  even  dilute  solutions  cause 
ischsemia  lasting  from  thirty  minutes  to  two  hours,  according  to  the 
rapidity  with  which  the  adrenaline  is  absorbed.  The  vessels  of  some 
organs  scarcely  contract  under  adrenaline,  and  no  benefit  is  to  be 
expected  from  its  application  in  haemorrhage  from  these;  spraying 
adrenaline  into  the  lungs  in  case  of  haemoptysis,  for  example,  is  quite 
useless,  and  similarly  haemorrhage  in  operations  on  the  brain  cannot 
be  controlled  by  it. 

The  constriction  of  the  vessels  in  a  part  to  which  adrenaline  is 
applied  retards  the  absorption  of  poisons  injected  with  the  adrenaline, 
and  at  the  same  time  permits  of  their  exercising  a  more  marked  local 
effect.  This  fact  has  been  utilized  in  surgery  to  prevent  the  absorp- 
tion of  cocaine  and  to  intensify  its  local  action,  and  the  method  has 
been  attended  with  most  encouraging  results.  A  few  drops  of  the  1 
per  mille  solution  are  added  to  the  Schleich's  solution  of  cocaine,  and 
blanching  of  the  tissues  results;  instead  of  cocaine,  any  of  its  substi- 
tutes may  be  used  as  adrenaline  does  not  interfere  in  any  way  with 
their  action. 

Bibliography. 

Oliver  and  Schafer.     Journ.  of  Physiol.,  xviii,  p.  230.    Biit.  McmI.  .loiirii.,  1901,  i.  i>.  1009. 
Szymonowicz.     Pfliiger's  Arch.,  Ixiv,  p.  97. 
Vincent.     Journ.  of  Physiol.,  xxii,  pp.  Ill  and  270. 
Gottlieb.     Arch.  f.  cxp.   Path.  u.  Pharm.,  xxxviii,  p.  99. 

Abel.  Ztschr.  f.  phys.  Chcm.,  xxviii,  p.  318.  Johns  Hopkins  Hospital  Hullctiii,  July, 
1897;    Nov.,  1901;    Feb.,  1902. 

Langlcy.     Journ.  of  Physiol.,  xxvii,  p.  237. 

Ambcrg.     Arch,  intcrnat.  de  Pharmacodyn.,  xi,  p.  37. 

Elliott.     Journ.  of  Phys.,  xxxii,  p.  401. 

Meltzer  and  Auer.     Amcr.  Journ.  of  Phys.,  xi. 

Brodie  and  Dixon.     Journ.  of  Physiol.,  xxx,  p.  491. 

Lawen.     Arch.  f.  cxp.  Path.  u.  Pharni.,  li,  p.  415. 

liniun.     Arch.  f.  klin.  ("hir.,  Ixix. 

Btiroer  ami  Dale.     Journ.  of  Piijsiol.,  xli,  p.  19. 

Olinwa.     \vv\\.  f.  cxp.  Patii.  u.  Piiarni.,  Ixvii,  p.  89. 

(Iramcntzski.  .   Biochcin.  Zcitschr.,  xlvi,  p.  ISG. 

Dixon  and  Rnnaom.     .lourn.  of  Piij'sio!.,  xlv,  p.  413. 

Trendelenbury.     Arch.  f.  cxjj.  Path.  u.  Pharnj.,  Ixiii,  p.  ICl. 


ERGOT  373 


XVI.    ERGOT. 


Ergot  is  a  parasitic  fungus  (Claviceps  purpurea)  which  grows  on  the 
rye  (Secale  cereale)  and  occasionally  on  other  kinds  of  grain;  more 
rarely  on  other  plants.  It  is  of  great  importance  in  therapeutics  and 
also  in  toxicology,  as  the  use  of  bread  and  meal  containing  it  has  fre- 
quently given  rise  to  widespread  epidemics. 

The  chemistry  of  ergot  has  been  the  subject  of  a  large  number  of 
investigations/  but  the  active  principles  have  only  been  established  by 
the  recent  work  of  Barger,  Dale  and  their  co-workers,  who  have  isolated 
several  alkaloids  from  the  fungus.  One  of  these,  Ergotinine,  C35H39O5N5, 
is  almost  inert,  but  its  hydrate,  Ergotoxine,  C35H41O6N5,  has  a  powerful 
action  on  the  tissues.  Either  alkaloid  can  be  readily  transformed  into 
the  other,  and  this  may  explain  many  of  the  discrepancies  in  the  litera- 
ture of  the  subject.  Tyramine  or  Hydroxyphenylethylamine,  OH.C6H4.- 
CH2CH2NH2,  and  Er gamine  or   Histamine    (/9-Iminazolylethylamine, 

\C.CH2.CH2.NH2)   along  with  several  less  important  bases 

such  as  Isoamylamine  and  Acetylcholine  are  also  present  in  ergot.  Several 
of  these  bases,  tyramine,  ergamine  and  isoamylamine  are  also  found  in 
putrefying  meat  and  are  derived  from  the  aminoacids,  tyrosin,  histidin 
and  leucin,  by  the  loss  of  the  carboxyl  group.  In  addition  to  the 
alkaloids,  ergot  contains  a  quantity  of  an  oil  and  other  inert  substances. 

Ergot  has  rarely  given  rise  to  serious  Acute  Poisoning  in  man,  but 
in  some  cases  in  which  it  was  taken  to  procure  abortion  the  symptoms 
consisted  in  collapse,  with  a  weak,  rapid  pulse,  tingling,  itching  and 
coldness  of  the  skin,  unquenchable  thirst,  vomiting  and  diarrhoea,  con- 
fusion or  unconsciousness,  haemorrhage  from  the  uterus,  abortion  and 
often  icterus.  Ecchymoses  were  found  in  the  subcutaneous  tissues 
and  in  many  internal  organs.  Occasionally,  after  a  single  small  dose, 
gangrene  has  supervened  in  small  areas  such  as  the  toe-nails. 

Given  in  therapeutic  doses  ergot  has  generally  no  effect  except  in 
pregnant  women,  in  whom  it  often  induces  contraction  of  the  uterus 
and  evacuation  of  its  contents.  In  some  cases  of  fatal  poisoning  no 
abortion  occurred. 

Chronic  Poisoning  was  formerly  not  uncommon,  and  in  fact  fre- 
quently gave  rise  to  widespread  epidemics,  from  the  use  of  bread 
containing  ergot  after  poor  harvests  and  especially  in  wet  seasons. 
Of  late  years  these  epidemics  have  become  rare  except  in  Russia,  but 
some  of  the  "plagues"  of  mediaeval  Europe  may  have  been  due  to 
ergot  poisoning. 

The  symptoms  of  ergotism  are  sharply  divided  into  two  groups: 
those  of  gangrene  and  those  of  nervous  disorders.  In  some  epidemics 
both  the  gangrenous  and  the  convulsive  forms  are  present,  but,  as  a 

1  These  have  generally  resulted  in  the  introduction  of  some  supposed  active  constit- 
uent, but  none  of  these  were  chemically  pure  and  the  names  have  now  only  historical 
interest.  The  best  known  of  these  names  are  ecboline,  ergotine,  sphacelinic  acid,  cornu- 
tine,  chrysotoxine,  secalintoxinc,  sphacelotoxine. 


374  SUBSTANCES  ACTING  AFTER  ABSORPTION 

U'ciieral  rulo,tlie  epidemics  in  Western  Euroi)c  were  almost  exclusively 
uauiiTenous  in  ty])e,  while  in  Eastern  Europe  the  c<)nvulsi^•e  form  almost 
invariably  pre\aile(l.  The  gaufjrene  is  fjenerally  developed  in  the  limbs, 
especially  in  the  fingers  and  toes;  sometimes  the  whole  arm  or  leg 
becomes  cold  and  anj^^sthetic,  dark  in  color,  and  then  dry,  hard  and 
shrunken,  and  falls  ofi"  with  little  or  no  pain  and  no  hjemorrhage.  Symp- 
toms of  such  severity  are  rare,  however,  and  in  milder  cases  only  the 
skin  necroses.  Gangrene  of  internal  organs  also  occurs,  resulting  in 
cataract  in  the  lens  of  the  eye,  or  ulcers  in  the  bowel  and  stomach,  and 
sometimes  afi'ecting  a  whole  organ  such  as  a  lung  or  the  uterus.  Abortion 
is  seldom  mentioned  in  the  accounts  of  chronic  ergot  poisoning,  and 
pregnancy  seems  in  many  cases  to  have  run  its  ordinary  course. 

In  spasmodic  ergotism  the  first  symptoms  are  depression,  weak- 
ness and  drowsiness,  often  with  headache  and  giddiness,  painful 
cramps  in  the  limbs  and  itching  and  formication  of  the  skin.  In 
severe  cases  paroxysmal  convulsions  set  in,  generally  clonic,  and  often 
epileptiform,  but  leaving  as  sequelae  contractures  in  the  limbs,  or  less 
often  in  the  trunk  muscles.  Some  intellectual  weakness  often  follows 
recovery  from  ergot  poisoning,  this  not  infrequently  amounting  to 
complete  dementia,  but  the  disease  was  immediately  fatal  in  a  large 
proportion  of  cases  in  earlier  times. 

In  mammals  treated  with  ergot,  restlessness,  salivation,  sometimes 
^'omiting  and  purging  have  been  observed.  Depression  and  weakness, 
ataxia  and  clonic  convulsions  follow  on  larger  doses,  which  prove 
fatal  by  paralyzing  the  respiratory  centre.  Gangrene  is  common  in 
tlie  pig,  in  which  the  ears,  the  extremities,  and  patches  of  the  skin  of 
the  trunk  become  dry  and  hard,  and  finally  fall  off.  Extravasations 
of  blood  into  the  stomach  and  bowel  and  other  organs  have  frequently 
followed  the  exhibition  of  ergot  in  mammals.  In  pregnant  animals 
abortion  is  often  induced,  but  not  invariably,  even  when  very  large 
doses  are  given. 

In  fowls  a  characteristic  train  of  symptoms  is  induced,  and  these 
animals  have  frequently  been  used  as  tests  for  the  activity  of  ergot 
j)reparati()ns.  The  cock  becomes  drowsy  and  dyspnoeic,  and  the  comb 
and  wattles  become  dusky  purple  in  color.  Vomiting  or  purging  may 
follow  and  a  curious  ataxia  is  observed,  the  animal  swaying  to  and  fro 
and  evidently  maintaining  its  balance  with  difficulty.  After  large  or 
repeated  doses  the  comb  becomes  dry  and  hard  and  falls  off,  and  a 
similar  gangrene  may  attack  the  legs,  tongue,  or  wings.  The  animal 
refuses  food  and  becomes  weak  and  somnolent,  but  may  recover  if  the 
treatment  be  stopped. 

The  gangrene  of  ergot  ])oisoning  arises  from  the  prolonged  con- 
striction of  the  vessels  by  the  ergotoxine.  It  is  uncertain  wliicli  principle 
induces  the  spasmodic  form,  but  it  is  not  unlikely  that  this  also  arises 
from  ergotoxine  acting  in  poorly  nourished  individuals. 

Action. — The  action  .of  ergot .  in  the  living  organism  has  only 
recently  been  elucidated  by  the  admirable  ex|ierimental  work  of  Dale, 
and  is  due  to  the  ergotoxine,  tyramine  and  ergamine.     The  first  two 


ERGOT  -wo 

of  these  resemble  adrenaline  in  some  of  their  effects,  and  like  it  act  on 
the  myoneural  junctions  of  the  true  sympathetic  ner\es.  But  w iiile 
adrenaline  stimulates  these  junctions  indiscriminately  whether  they  are 
motor  or  inhibitory  in  character,  tyramine  appears  to  aft'ect  the  motor 
ones  more  than  the  inhibitory,  while  ergotoxine  does  not  act  on  the 
inhibitory  junctions  at  all.  And  ergotoxine,  while  stimulating  the 
motor  myoneural  junctions  in  small  doses,  paralyzes  them  in  larger 
amounts.  These  bases  are  much  less  powerful  than  adrenaline,  but 
their  effects  last  longer  and  can  be  elicited   by   hypodermic   injection 

Fig.  36 


Leg  volume 


—120  mm. 
—lie 

B.r. 


__l|_J_J l_! \ I I I I L 

.4. 


B 


Figures  illustrating  the  effects  of  ergotoxine  on  the  blood-pressure  (Dale).  In  A  the 
injection  induces  a  rise  of  blood-pressure  (B.P.)  with  constriction  of  the  vessels  of  the 
leg.  In  5  a  large  dose  of  ergotoxine  had  been  injected  previously,  and  adrenaline  injected 
at  the  point  indicated  now  causes  a  fall  of  blood-pressure  with  dilatation  of  the  intes- 
tinal vessels. 

or  even  by  administration  by  the  mouth.  Tyramine  is  prol)ably  of 
less  importance  in  the  action  of  ergot  than  ergotoxine,  which  along 
with  ergamine  is  responsible  for  the  chief  effects  of  the  drug.  Ergamine 
differs  from  the  other  bases  in  acting  not  on  the  nerve  junctions,  but 
on  the  unstriated  muscle  cells  directly,  and  its  action  varies  consider- 
ably in  different  species  of  animals  and  even  in  different  organs  of  the 
same  animal. 

Circulation. — Ergotoxine  or  tyramine  injected  intravenously  causes 
an  abrupt  rise  in  blood-pressure  which  is  obviously  due  to  action  on  the 
peripheral  vessels,  for  it  occurs  after  section  of  the  splanchnic  nerves, 


376 


SUBSTANCES  ACTING  AFTER  ABSORPTION 


and  is  accompanied  by  constriction  of  tlie  vessels  of  the  abdominal 
cavity  and  the  limbs,  as  may  be  shown  by  oncometer  and  plethysmo- 
•iraphic  records  (Fig.  36,  A).  The  heart  is  often  accelerated  at  first  and 
then  slowed,  partly  from  the  vagus  centre  being  stimulated  by  the 
high  blood-pressure  and  partly  by  a  direct  action  on  the  heart  muscle. 
Sometimes  the  slowing  of  the  heart  may  be  so  marked  as  to  lower  the 
blood-pressure  and  thus  to  conceal  the  effects  of  the  vaso-constriction 

on  the  tracing. 

Fig.  .37 


dolled 


'  I  I  I  I  I  I  I  I  I  I  I  I  I  I  I  I  I  I  I  I 


The  action  of  ergamine  on  the  blood-pressure  (B.P.)  and  on  the  vohime  of  the  intes- 
tine and  kidney  in  the  cat.  The  injection  causes  a  marked  fall  in  the  blood-pressure  which 
is  due  to  dilatation  of  intestinal  vessels.     The  kidney  vessels  arc  constricted.     (Dale.) 

The  rise  in  })ressure  is  to  be  ascribed  to  stimulation  of  the  constric- 
tor nerve  terminations  in  the  vessel  walls  and  is  strictly  analogous  to 
that  observed  under  adrenaline.  The  extent  to  which  it  is  develoi)ed 
varies  in  different  animals,  being  well  marked  in  the  cat,  dog  and 
fowl  and  observed  only  with  difficulty  in  the  rabbit  and  monkey. 

The  efl'ects  of  ergamine  on  the  vessels  vary  in  ditVerent  animals;  in  the 
dog  and  cat  it  causes  a  profound  fall  in  blood-i)ressure  frtnn  dilatation 
of  the  peripheral  vessels,  while  in  the  rabbit  it  tends  to  constrict  them. 
In  both  cases  the  action  is  a  direct  one  on  the  vessel  walls,  but  it  is  un- 
certain whether  the  neuromuscular  apparatus  is  affected  or  the  muscle 
alone.  The  vessels  of  the  cat  and  dog  perfused  with  l^inger's  solution 
contract  under  ergamine,  thus  reversing  their  behavior  in  the  intact 
animal.  And  some  of  the  vessels,  notably  those  of  the  lungs  and  of  the 
heart  are  constricted  by  ergamine  when  it  is  injected  intravenously, 
and  circulates  in  the  blood. 


ERCOT  377 

Tlie  effects  of  ergot  or  the  blood-pressure  vary  according  to  the 
relative  amount  of  bases  present.  If  ergotoxine  and  tyraniine  are 
present  in  large  amounts,  the  blood-pressure  rises,  while  if  ergamine 
predominates,  it  may  fall,  at  any  rate  in  some  animals.  As  a  general 
rule  it  first  falls  rapidly  and  deeply  and  then  rises  to  slightly  above  the 
normal. 

Tyramine  constricts  the  vessels  when  it  is  applied  locally,  but  ergo- 
toxine has  less  effect.  The  absorption  is  not  so  much  retarded  as 
by  adrenaline  therefore,  and  ergot  action  may  thus  be  elicited  by 
hypodermic  or  by  oral  administration  of  the  drug. 

The  heart  is  not  acted  upon  so  strongly  as  the  vessels  by  the  ergot 
bases.  Tyramine  affects  it  in  exactly  the  same  way  as  adrenaline,  and 
ergotoxine  and  ergamine  strengthen  the  contractions  and  slow  the 
rhythm  in  some  degree;  it  is  uncertain  how  far  this  arises  from  direct 
action  on  the  cardiac  muscle  and  how  far  the  accelerator  terminations 
are  involved.  Crude  ergot  preparations  generally  slow  and  strengthen 
the  heart  when  injected  intravenously;  sometimes  a  muscarine  action 
is  induced  by  the  presence  of  acetylcholine.  The  terminations  of  the 
inhibitory  nerves  of  the  heart  are  not  paralyzed  or  weakened  in  any 
way  by  ergot. 

Stomach  and  Intestine. — Ergotoxine  in  small  doses  has  little  effect 
on  the  movements  of  these  organs,  while  ergamine  causes  rapid  peri- 
staltic contractions  from  direct  action  on  the  unstriated  muscle;  tyra- 
mine tends  to  arrest  all  movement  in  the  same  way  as  adrenaline  by 
stimulating  the  terminations  of  the  inhibitory  sympathetic  neurons; 
under  ergot  vomiting  and  diarrhoea  often  occur  in  animals,  probably 
from  the  action  of  ergamine;  in  man  the  action  on  the  digestive  organs 
is  seldom  noticeable. 

The  Pupil  undergoes  a  powerful  constriction  when  ergot  is  injected 
intravenously,  sometimes  after  a  momentary  dilatation.  This  con- 
striction is  not  affected  by  atropine  and  arises  from  the  direct  action 
of  ergotoxine  on  the  muscle  fibre.  Tyramine,  like  adrenaline,  tends  to 
dilate  the  pupil  but  is  not  present  in  sufficient  amount  to  withstand 
the  more  powerful  ergotoxine  effect.  Ergamine  constricts  the  pupil, 
apparently  from  some  central  action. 

The  Respiration  is  curiously  affected  by  ergamine  in  the  guinea-pig 
and  rabbit,  in  which  it  induces  spasm  of  the  bronchial  muscle  and 
consequent  asphyxia;  the  lungs  are  found  fully  dilated  and  do  not 
collapse,  because  the  air  cannot  escape  through  the  narrowed  bronchi. 
This  action  on  the  bronchi  is  less  marked  in  other  animals,  and  asphyxia 
does  not  occur  in  them  from  this  cause. 

The  most  important  effect  of  ergot,  however,  is  exerted  on  the 
Uterus,  in  which  it  causes  a  powerful  contraction  which  lasts  for  a  short 
time  and  is  followed  by  a  slow  relaxation  interrupted  by  numerous  new 
contractions,  a  lasting  effect  on  the  irritability  being  induced.  All 
three  alkaloids  contribute  to  this  effect,  though  in  unequal  measure; 
thus  ergotoxine,  stimulating  the  motor  myoneural  junctions,  causes 
contraction;  ergamine  acting  directly  on  the  muscle  fibres  has  a  similar 


578 


SUBSTAXCES  ACTING  AFTER  ABSORPTION 


effect,  though  it  tends  to  cause  tonic  contraction  rather  than  alternate 
contraction  and  rehixation;  tyramine,  acting  on  both  motor  and 
inhil)it()ry  norvc  ai)i)aratus,  contracts  tlic  pregnant  uterus  in  all  animals, 
hut  in  the  non-pregnant  cat  may  relax  it  if  given  alone;  given  along  with 
ergotoxine  and  tyramine,  however,  its  feeble  inhibitory  action  hardly 
comes  into  play. 

The  uterus  thus  reacts  to  ergot  in  a  way  precisely  analogous  to  the 
arterioles,  and  it  is  noteworthy  that  from  the  uterus  alone  any  very 
ob^-ious  symptoms  are  elicited  by  therapeutic  doses.  For  the  alimen- 
tary tract  is  but  little  affected,  and  the  rise  of  blood-pressure  is  not 
easily  observable  in  the  circumstances  in  which  ergot  is  usually  exhib- 
ited. The  contraction  of  the  uterus  in  pregnant  animals  causes  the 
descent  of  the  foetus  toward  the  os,  and  in  suitable  doses  ergot  induces 
abortion.  If  the  dose  injected  is  small,  the  rhythmic  contractions 
are  accelerated  and  strengthened,  or  if  the  uterus  is  at  rest,  ergot  may 
arouse  it  to  rhythmic  contraction.  As  the  dose  is  increased,  the  con- 
tractions become  more  powerful  and  last  a  longer  time,  until  with  a 
large  injection  the  uterus  may  contract  very  powerfully  and  remain 
in  this  position  for  many  minutes. 

Fig.  38 


Tr.icing  of  the  movements  of  the  uterus  under  ergot  injected  intravenously  at  the  point  E. 
Contraction  is  indicated  by  an  upward  movement  of  the  lever. 


The  secondary  paralyzing  action  of  ergotoxine  on  the  myoneural  junctions 
is  elicited  only  by  very  large  doses  and  does  not  occur  in  the  therapeutic  use 
of  ergot.  Very  large  quantities  of  ergot  often  elicit  this  effect  in  experiments, 
however.  This  paralysis  affects  only  the  motor  sympatlictic  neurons,  while 
tlie  inliihitory  ones  are  left  unaffected  and  stimulation  of  a  mixed  niotor  and 
iiiliihitory  nerve,  or  tlie  injection  of  adrenaline,  now  causes  inliihition  only 
Thus,  after  a  large  dose  of  ergotoxine,  adrenaline  lowers  the  l)lood-i)ressure 
(Fig.   :iG,  B),  wiiile   previously   it  increased  it  by  stimulating  the  constrictor 


ERGOT  379 

nerve  ends;  these  are  now  unable  to  react  from  the  paralyzing  action  of  ergo- 
toxine,  but  the  dilator  nerve  ends  are  still  unharmed,  and  adrenaline  stimulat- 
ing them  dilates  the  vessels.  Adrenaline  also  acted  on  the  dilators  before  the 
ergotoxine  injection,  but  the  effect  of  this  stimulation  was  masked  by  the 
sinuiltaneous  stimulation  of  the  more  powerful  constrictors.  The  same  reversal 
of  effect  by  ergotoxine  is  seen  if  the  splanchnic  nerves  be  stinmlated.  The 
accelerator  cardiac  fibres,  the  motor  splanchnic  fibres  to  the  intestinal  sphincters 
and  bladder  and  other  similar  motor  sympathetic  fibres  are  similarly  paralyzed 
by  ergotoxine  in  large  doses,  and  stimulation  of  the  nerves  or  the  injection 
of  adrenaline  has  now  no  effect  on  them  The  fibres  from  the  cranial  and  sacral 
nerves,  however,  are  uninjured.  Similarly,  stimulation  of  the  cervical  sym- 
pathetic no  longer  dilates  the  pupil  or  elicits  salivation  in  ergotoxine  poison- 
ing because  the  connection  with  the  muscle  and  gland  is  broken,  but  the  motor 
oculi  and  chorda  tympani,  being  cranial  nerves,  remain  normal.  Both  motor 
and  inhibitory  nerves  of  the  uterus  are  sympathetic,  and  ergotoxine  in  large 
amounts  paralyzes  the  motor  while  leaving  the  inhibitory  intact :  stimulation  of 
the  hypogastric  nerve  or  adrenaline  now  causes  inhibition  and  relaxation. 

Preparations. 

U.  S.  p. — Ergota,  ergot  of  rye,  the  sclerotium  of  Claviceps  purpurea  replacing 
the  grain  of  rye.    When  more  than  one  year  old,  it  is  unfit  for  use. 

Extradum  Ergotce,  0.25  G.  (4  grs.). 

Fluidextractum  Ergot.e,  2  c.c.  (30  mins.). 

B.  P. — Ergota,  the  sclerotium  of  Claviceps  purpurea,  originating  in  the  ovary 
of  Secale  cereale.    It  should  not  be  used  if  more  than  a  year  old.    15-60  grs. 

Extractum  Ergotce  (Ergotin),  2-8  grs. 

ExTRACTUM  Ergots  Liquidum,  10-30  mins. 

Tinctura  Ergotce  Ammoniata,  \-\  fl.  dr. 

Injectio  Ergotce  IIypodermica,  5-10  mins.  (subcutaneously).  It  contains 
1  part  of  the  extract  in  3  parts  of  water  and  should  be  freshly  prepared. 

The  fluid  or  liquid  extracts  and  the  hypodermic  injection  are  the  best  of 
the  preparations.  A  very  large  number  of  preparations,  such  as  ergotin,  ergo- 
tinic  acid,  sclerotinic  acid,  cornutine,  etc.,  are  simply  more  or  less  purified 
extracts  and  have  no  advantage  over  the  pharmacopoeial  preparations. 

The  pure  alkaloids,  ergotoxine  phosphate,  tyramine,  and  ergamine,  have 
been  put  on  the  market  and  are  used  to  a  limited  extent,  and  a  solution  of  all 
three  is  also  available  under  the  name  of  ernutine. 

The  crude  preparations  vary  greatly  in  activity  and  appear  to  deteriorate 
rapidly  on  keeping.  At  present  they  can  be  standardized  only  by  comparing 
their  activity  on  the  uterus  or  blood-pressure  of  animals  with  that  of  a  standard 
preparation  or  with  that  of  the  alkaloids. 

Therapeutic  Uses. — Ergot  is  used  very  largely  in  obstetrics  to  pro- 
mote the  contraction  of  the  uterus,  but  considerable  divergence  is  met 
with  in  the  views  of  different  authorities  as  to  the  special  indications 
for  its  exhibition.  Thus,  those  who  beheve  that  ergot  increases  the 
irritability  of  the  uterus  and  produces  rhythmical  contraction  without 
tetanus,  advise  that  it  be  given  wdienever  the  pains  seem  insufficient, 
and  more  especially  wOien  this  occurs  in  the  later  stages  of  labor. 
Others  are  possessed  with  an  exaggerated  apprehension  of  the  pro- 
longed uterine  contractions,  which  they  consider  delay  labor  and  tend 
to  cause  asphyxia  in  the  child,  and  therefore  advise  that  ergot  be  used 
only  to  preserve  the  uterus  in  a  contracted  condition  after  the  child 
and  placenta  have  been  expelled.    In  every  case  the  attendant  should 


380       SUBSTANCES  ACTING  AFTER   ABSORPTION 

of  course  sjitify  himself  before  j^iviiifj  ergot  of  the  absence  of  all 
actual  iniixMlinuMits  to  the  passage  of  the  chilrl,  such  as  contracted 
j)clvis,  abnormal  presentation,  or  great  rigidity  of  the  soft  parts,  and 
when  it  is  administered  before  the  head  emerges,  the  dose  ought  to  be 
small,  as  otherwise  the  tonic  contraction  may  be  induced.  When  the 
head  is  about  to  emerge,  on  the  other  hand,  a  large  dose  may  be  given 
to  promote  the  permanent  contraction  of  the  uterus  and  thus  to  prevent 
jjost-partum  hsemorrhage.  When  the  latter  has  once  set  in,  ergot  is 
of  less  immediate  service,  as  it  is  slowly  absorbed,  and  no  effects  follow 
for  some  twenty  minutes  or  more.  Whenever  there  is  any  reason  to 
fear  that  weakness  of  the  uterine  contraction  and  haemorrhage  may 
set  in  after  the  expulsion  of  the  child,  ergot  ought  to  be  given  when 
the  head  emerges,  and  many  gynecologists  recommended  this  as  a 
routine  treatment. 

Ergot  hinders  post-partum  haemorrhage,  chiefly  by  promoting  the 
contraction  of  the  uterus.  In  other  forms  of  haemorrhage — from  the 
stomach,  intestines,  kidneys,  lung  or  uterus — in  w^hich  the  bleeding 
point  cannot  be  reached,  it  is  often  advocated  in  the  belief  that  it  con- 
tracts the  walls  of  the  vessels  and  thus  arrests  the  flow  of  blood. 
These  haemorrhages  so  often  cease  spontaneously  that  it  is  difficult  to 
estimate  the  value  of  any  remedy,  but  it  may  be  questioned  whether 
ergot  merits  its  reputation  in  these  cases.  There  is  no  reason  to  suppose 
that  a  more  intense  action  is  exerted  on  a  ruptured  vessel  than  on  the 
uninjured  ones  of  other  organs;  but  unless  this  is  the  case  the  use  of 
ergot  may  be  rather  harmful  than  remedial,  for  any  increase  in  the 
general  blood-pressure,  such  as  would  follow  the  contraction  of  the 
vessels  throughout  the  body,  must  increase  the  escape  of  blood  from  the 
injured  vessel.  The  use  of  ergot  in  pulmonary  htemorrhage  may  be 
taken  as  an  example:  here  ergot  contracts  the  vessels  very  distinctly, 
and  if  the  lesion  lies  beyond  the  part  of  the  vessel  which  is  contracted, 
that  is,  if  the  bleeding  is  capillary,  the  slower  circulation  may  be  bene- 
ficial ;  but  the  constriction  of  the  vessels  increases  the  pressure  in  the 
arterioles,  and  if  the  bleeding  is  arterial  this  augmented  pressure  nuiy 
actually  increase  it.  Most  clinical  observers  doubt  the  efficacy  of  ergot 
or  any  other  vasoconstrictor  in  arresting  internal  luemorrhage  except 
from  the  uterus,  and  some  advise  the  opposite  treatment  with  vaso- 
dilators to  reduce  the  blood-pressure  (see  Nitrite  group).  The  essential 
treatment  is  rest  with  or  without  morphine.  In  these  cases,  as  in 
labor,  the  fluidextract  of  ergot  is  often  given  by  the  mouth,  but  this 
extract  or  the  special  preparation  of  the  B.  P.  is  sometimes  injected 
with  the  hypodermic  needle.  It  is  irritant,  and  ought,  therefore,  to 
be  injected  deeply  into  the  muscle,  rather  than  into  the  sul)cutaneous 
tissues. 

The  effect  of  ergot  in  inducing  contraction  of  the  uterus  has  been 
used  in  the  treatment  of  subinvolution  and  of  myomata  of  that  organ; 
the  involution  of  the  uterus  certainly  seems  to  be  favored  by  it,  but 
the  results  in  tumor  are  more  ojkmi  to  (luestion.  In  any  case  the 
prolonged  treatment  of  this,  or  of  any  other  condition,  with  ergot  is 


PITUITARY  EXTRACT  381 

to  be  deprecated,  for  if  the  drug  is  active  at  all,  it  may  induce  gan- 
grene or  spasmodic  ergotism.  The  same  criticism  might  be  applied 
to  the  ergot  treatment  of  a  number  of  other  diseases,  such  as  aneurism, 
diabetes,  or  pneumonia;  and  in  addition,  it  does  not  seem  to  have  any 
greater  effect  in  these  than  many  other  less  dangerous  remedies,  which 
have  been  equally  vaunted  as  specifics,  and  have  been  found  equally 
valueless. 

Bibliography. 

Dais:     Journ.  of  Phys.,  xxxiv,  p.  163. 

Dale  and  Dixon.     Ibid.,  xxxix,  p.  25. 

Barger  and  Dale.     Biochemical  Journ.,  ii,  p.  240.    Arch.  f.  exp.  Path.,  Ixi,  p.  113. 

Dale  and  Laidlaw.     Journ.  of  Physiol.,  xli,  p.  318;   xliii,  p.  182. 

XVn.  PITUITARY  EXTRACT. 

The  extract  of  the  pituitary  body  was  shown  by  Oliver  and  Schaefer 
to  exercise  a  pronounced  effect  when  it  was  injected  intravenously;  the 
anterior  lobe  proved  devoid  of  this  action,  the  active  substance  appear- 
ing to  occur  only  in  the  posterior  lobe  or  infundibulum  and  in  the  inter- 
mediate tissue,  which  may  probably  be  regarded  as  its  seat  of  origin. 
The  nature  of  this  active  principle  is  still  undetermined,^  but  it  is  a 
comparatively  simple  body  which  can  be  dialyzed  and  boiled  without 
losing  its  efficiency, 

Action.^ — The  administration  by  the  mouth  of  the  dried  gland  or  its 
extract  is  not  attended  with  any  obvious  result,  while  the  intravenous 
injection  of  the  aqueous  extract  causes  pronounced  effects  in  a  number 
of  organs,  especially  on  those  containing  involuntary  muscle. 

Circulation. — When  the  extract  is  injected  intravenously,  the  blood- 
pressure  rises  rather  slowly  and  remains  elevated  for  some  time.  The 
rise  is  sometimes  preceded  b}'  an  abrupt  fall,  but  this  is  probably  due 
to  some  impurity  and  not  to  the  essential  principle.  The  rise  in  pressure 
is  due  to  constriction  of  the  peripheral  arterioles,  as  is  shown  by  the 
lessened  volume  of  the  organs.  And  as  this  constriction  occurs  after 
the  vaso-constrictor  nerves  have  been  divided  and  even  after  their  con- 
nection with  the  muscular  coats  of  the  arterioles  has  been  interrupted 
by  ergotoxine,  the  pituitary  substance  must  act  directly  on  the  muscle 
fibre.  The  rise  in  pressure  under  pituitary  extract  is  smaller  and  less 
abrupt  than  that  under  adrenaline,  but  it  is  maintained  longer.  The 
constrictor  action  on  the  vessels  may  be  shown  by  perfusing  them  with 
saline  containing  pituitary  extract,  when  the  venous  outflow  is  at  once 
reduced.  All  the  arterioles  examined  appear  to  be  constricted  when  thus 
perfused,  but  in  the  body  they  vary  in  their  response,  some  being 
narrowed  more  than  others  and  the  renal  vessels  even  being  dilated. 

'  Fiihner  has  recently  investigated  the  action  of  a  number  of  substances  obtained  from 
the  extract,  four  of  which,  he  states,  possess  the  action  of  the  glancf  in  greater  or  less 
degree.  The  description  of  these  supposed  active  principles  is  not  convincing,  however, 
and  suggests  that  they  may  owe  their  effects  to  their  each  being  contaminated  with  one 
unknown  and  very  powerful  substance. 


.382       SUBSTANCES  ACTING  AFTER  ABSORPTION 

The  heart  is  generally  slowed  by  the  injection,  and  this  partly 
through  direct  action  on  the  cardiac  muscle,  and  in  smaller  part  from 
inhibitory  action;  the  slight  inhibitory  stimulation  may  perhaps  arise 
from  the  increased  blood-pressure  flooding  the  brain  and  arousing  the 
inhibitory  centre.  But  the  extract  also  slows  the  excised  heart  perfused 
with  Ringer's  solution,  which  indicates  that  the  muscle  is  directly 
aflPected.  The  sudden  fall  of  l)lood-pressure  which  is  sometimes  observed 
immediately  after  the  injection  appears  to  be  due  to  this  cardiac 
depressant  action. 

After  the  blood-pressure  has  returned  to  its  normal  height,  a  second 
injection  of  pituitary  extract  is  found  to  have  no  effect  or  a  much 
slighter  one  than  the  first,  the  vessel  walls  apparently  having  lost  their 
power  of  response  to  the  active  principle.  Or  the  blood-pressure  may 
fall  instead  of  rising,  owing  to  the  presence  of  depressor  substances 
in  the  preparation. 

Fig.  39 


Contraction 


III  iiiiinii  III  iiiiiiiiiiiiiniiinininiii  iiimmniiiiinilUlltll. 

Contraction  of  the  isolated  uterus  suspended  in  Ringer's  solution;    pituitary  extract  was 

added  at  P.     (Dale.) 

Respiration. — Fiihner  states  that  the  respiration  often  fails  immedi- 
atcl.N-  after  the  injection  and  then  recommences  with  feeble  movements 
which  increase  in  depth  and  then  gradually  diminish  again.  This 
alternate  waxing  and  waning  of  the  respiratory  movements  may  be 
repeated  several  times.  It  is  said  to  arise  in  part  from  constriction  of 
the  bronchi  and  in  part  from  the  changes  in  the  blood-pressure.  There 
is  no  reason  to  believe  that  the  respiratory  centre  is  affected  directly. 

The  Stomach  and  Intestine  are  aroused  to  stronger  contractions  under 
pituitary  extract  and  their  tone  is  increased,  the  relaxation  IxMUg  nuich 
less  complete.    The  bladder  also  undergoes  similar  changes. 

The  Uterus  contracts  more  strongly  and  relaxes  less  completely  after 
pituitary  extract  (Dale),  and  this  change  dilVers  from  that  seen  under 
adrenaline  in  that  the  stimulating  action  occurs  in  all  animals,  whether 
pregnant  or  not,  and  therefore  cannot  be  attributed  to  action  on  the 
nervous  mechanism  but  must  arise  from  direct  muscular  effect.     This 


PITUITARY  EXTRACT  383 

action  on  the  iiterns  follows  from  the  hypodermic  as  well  as  from  the 
intra venons  injection  of  pituitary  extract,  and  is  more  marked  than  the 
motor  action  on  the  alimentary  tract. 

The  Pupil  appears  to  vary  in  its  reaction  and  shows  no  very  marked 
change  as  a  general  rule;  in  the  excised  eye  of  the  frog  some  observers 
obtained  dilatation,  other  contraction;  in  the  rabbit  contraction  generally 
occurs. 

Kidney. — One  of  the  earlier  observations  was  that  pituitary  injection 
was  followed  by  a  profuse  secretion  of  urine,  generally  accompanied 
by  dilatation  of  the  renal  vessels  and  an  increase  in  the  volume  of  the 
kidney.  It  is  still  undetermined  how  the  diuresis  is  effected;  the  increase 
in  blood-pressure  with  dilatation  of  the  renal  vessels  seems  sufficient 
to  explain  it  in  ordinary  cases,  but  diuresis  may  occur  without  any  rise  of 
pressure  and  also  witliout  dilatation  of  the  vessels,  and  it  has  been  ob- 
served in  some  cases  after  a  second  injection  which  depressed  the  circula- 
tion rather  than  increased  it.  Schaefer  therefore  holds  that  the  pituitary 
extract  stimulates  the  renal  cells  to  increased  activity  and  that  the 
dilatation  of  the  vessels  is  rather  the  result  than  the  cause  of  the  diuresis. 
The  diuresis  occurs  wdien  the  extract  is  administered  by  the  mouth  or 
hypodermically,  though  with  less  regularity  than  after  intravenous 
injection.  In  a  considerable  number  of  cases  glycosuria  sets  in  after 
an  injection;  it  is  unknown  whether  this  is  a  sequel  of  the  diuresis  or 
of  a  more  specific  action. 

Milk-secretion. — One  unique  property  of  pituitary  extract  is  its  power 
of  increasing  the  secretion  of  the  mammary  glands.  No  other  drug 
approaches  it  in  this  galactagogue  effect.  The  rate  of  secretion  may  be 
increased  as  much  as  eighty  times  by  an  intravenous  injection  of  pitui- 
tary extract  and  Schaefer  states  that  even  the  glands  of  a  non-pregnant 
cat  may  be  induced  to  secrete  some  serous  fluid  under  its  influence. 
It  is  probable  that  pituitary  extract  does  not  actually  increase  the 
amount  of  milk  formed,  but  merely  causes  its  rapid  expulsion  by  caus- 
ing the  unstriated  muscle  of  the  gland  to  contract.  While  the  secretion 
is  increased  immediately,  the  total  amount  of  milk  per  day  is  not  aug- 
mented in  cows.  In  the  human  subject  pituitary  extract  injected 
intramuscularly  causes  tingling  in  the  breasts  and  then  free  secretion. 
The  extract  of  the  pituitary  of  birds  and  fishes  is  also  galactagogue  in 
mammals.^ 

The  Central  Nervous  System  does  not  seem  to  participate  in  the 
action  of  pituitary  extract  except  after  very  large  doses,  which  are 
followed  by  some  somnolence  and  muscular  weakness. 

The  action  of  pituitary  extract  is  apparently  a  direct  one  on  the 
terminal  organs  in  each  case  and  not  on  the  nervous  mechanism. 
The  failure  of  a  second  injection  to  induce  effects  comparable  to  the 
original  one  has  not  been  explained  in  any  way.  The  most  typical 
effects  are  obtained  by  the  intravenous  injection  of  the  extract,  but 

'  The  other  known  galactagogues  are  extracts  of  the  corpus  kiteum,  pineal  gland,  invol- 
uting uterus,  and  of  the  lactating  mammary  gland  itself,  and  these  are  less  powerful 
than  pituitary  extract. 


384  SUBSTANCES  ACTING  AFTER  ABSORPTION 

subcutaneous  injection  also  elicits  them  in  a  less  marked  degree.  Little 
or  no  effect  follows  the  administration  of  the  gland  or  its  extracts  by 
the  mouth  except  more  or  less  marked  diuresis. 

General  Metabolism. — The  effects  of  the  pituitary  extract  on  the 
metabolism  have  not  been  adequately  examined.  It  is  not  found  that 
the  growth  of  young  animals  is  materially  altered  by  its  administration 
with  the  food. 

The  Excretion  of  the  pituitary  principle  appears  to  be  slow  and  to  be 
performed  by  the  kidney. 

Preparations. — No  preparations  of  the  pituitary  body  are  as  yet 
official.  Various  purified  extracts  of  the  posterior  lobe  are  on  the  market 
under  the  names  of  Pituitrin,  Infundibulin,  Hypophysin,  Pituglandol 
and  Hj'pophysin  sulphate,  and  are  used  for  hypodermic  injection. 
The  amount  of  active  principle  in  these  preparations  is  unknown,  but 
most  of  them  are  assayed  by  their  effects  on  animals  and  the  dose 
for  hypodermic  injection  is  0.6-1  c.c.  (10-15  mins.). 

Therapeutic  Uses. — Pituitary  preparations  have  been  extensively  used 
in  obstetrics  in  order  to  arouse  and  strengthen  the  contractions  of 
the  uterus.  The  effects  come  on  about  3-5  minutes  after  the  sub- 
cutaneous injection;  the  contractions  of  the  uterus  set  in  moderately 
but  increase  in  strength  and  the  interval  between  the  pains  is  shortened. 
The  contractions  themselves  are  of  shorter  duration  but  stronger  and 
in  some  instances,  at  any  rate,  the  relaxation  is  less  complete  between 
the  pains.  The  extract  is  used  chiefly  to  arouse  an  inert  uterus  but  has 
also  been  injected  after  delivery  in  order  to  prevent  post-partum  hjiemor- 
rhage  by  inducing  contraction.  It  is  used  as  a  substitute  for  ergot  in 
short,  and  is  said  to  be  less  liable  to  cause  tonic  contraction  of  the  uterus, 
though  this  may  prove  to  be  erroneous  on  further  experience.  It  may 
be  injected  in  one  or  in  several  doses  and  as  much  as  3  c.c.  of  pituitrin 
has  been  used  without  injury. 

The  diuretic  action  of  pituitrin  is  less  available  for  clinical  use,  as  the 
repeated  injection  of  the  drug  is  scarcely  possible  and  it  has  little  effect 
when  given  by  the  mouth.  Its  effect  in  increasing  the  milk  secretion 
is  also  not  yet  made  use  of  in  medicine  and  the  same  objection  holds 
against  its  employment  for  this  purpose.  It  has  been  employed  in  some 
cases  of  shock  to  raise  the  blood-pressure.  It  seems  unlikely  to  be  of 
value  to  arrest  lunemorrhage  owing  to  its  raising  the  blood-pressure. 

In  the  failure  of  the  intestinal  i)eristalsis  which  sometimes  follows  ex- 
tensive operation,  pituitary  extract  has  been  injected  with  good  results. 

Pituitary  extract  is  stated  to  have  been  beneficial  in  certain  forms  of 
atrophj'^  of  the  hypophysis  and  in  symptoms  which  are  referred  to  a 
lowered  efficiency  of  the  gland.  Very  large  amounts  have  been  given 
in  some  of  those  cases  without  any  deleterious  efi'ects. 

Other  Organic  Extracts  (Organotherapy). 

In  recent  years  numerous  extracts  of  animal  organs  have  been  intro(hiced 
into  thcrai)eutics,  but  with  the  exception  of  the  preparations  of  the  supra- 


IIYDKASTINE  AND  HYDRASTININE  385 

renal,  i)ituitary,  and  thyroid  glands,  they  have  proved  disapi)oiMtnicnts.  The 
theory  on  which  many  of  these  have  been  evolved,  shows  little  advance  upon 
the  belief  of  the  savage  that  the  courage  of  the  lion  may  be  acquired  by  eating 
the  animal's  heart,  and  the  clinical  observations  which  have  been  cited  to  sup- 
port their  use,  have  generally  been  of  an  equally  primitive  order.  The  atrophy 
or  destruction  of  certain  organs  unquestionably  gives  rise  to  marked  and 
even  fatal  symptoms:  for  example,  removal  of  the  pancreas  is  followed  by 
diabetes,  atrophy  of  the  suprarenal  bodies  leads  to  Addison's  disease,  and  cas- 
tration involves  certain  structural  changes  in  distant  organs.  But  in  none  of 
these  instances  can  these  sequelte  be  averted  by  the  use  of  the  extract  of  the 
excised  organs:  they  may  possess  internal  secretions,  but  these  cannot  be 
utilized  in  therapeutics,  possibly  because  of  their  rapid  destruction.  Probably 
no  more  fruitful  source  of  quackery  exists  than  in  the  exploitation  of  these 
so-called  remedies,  and  among  them  all  the  extracts  of  the  testicles  and  ovaries 
stand  preeminent:  introduced  by  Brown-Sequard  in  1889  on  insufficient  obser- 
vations, the  testicular  extract  has  been  employed  as  a  sort  of  panacea,  which 
among  other  qualities,  restored  to  age  the  fire  and  vigor  of  youth.  All  accurate 
observations  agree  that  this  extract  is  entirely  devoid  of  value  in  therapeutics. 
Further  advance  is  to  be  looked  for  in  the  use  of  these  extracts,  but  can  only 
be  made  through  careful  observation  and  experiment,  which  alone  has  given 
us  the  useful  remedies  of  this  class  which  are  now  available.  The  indiscrimi- 
nate and  haphazard  use  of  these  organ-extracts  in  every  sort  of  disease  has  not 
led  to  any  progress  in  the  past,  and  will  hardly  be  more  successful  in  the  future. 

Bibliography. 

Schafer  and  Oliver.     Journ.  of  Phys.,  xviii,  p.  277. 

Howell.     Journ.  of  Exp.  Med.,  iii,  p.  245. 

Schafer  and  Vincent.     Journ.  of  Physiol.,  xxv,  p.  87. 

Schafer  and  Herring.     Phil.  Trans.  Roy.  Soc,  B'.  199,  p.  1. 

Dale.     Biochem.  Journ.,  iv,  p.  427. 

Schafer,     Proc.  Roy.  Soc,  B.  Ixxxi,  p.  442. 

Frohlich  u.  Pick.     Arch.  f.  exp.  Path.  u.  Pharm.,  Ixxiv,  pp.  92,  1U7,  114. 

Filhner.     Zeitschr.  f.  d.  ges.  exp.  Med.,  i,  p.  397. 

Mackenzie.     Quart.  Journ.  Exp.  Physiol.,  iv,  p.  305. 

Wiggers.     Amer.  Journ.  Med.  Sci.,  April,  1911. 

XVm.    HYDRASTINE  AND  HYDRASTININE. 

Hydrastine  is  an  alkaloid  which  occurs  in  Hydrastis  Canadensis  (Golden  Seal) 
along  with  two  other  alkaloids,  Berherine  and  Canadine.  Hydrastine  (CH2.O2- 
C9H7NCH3.C10H9O4)  is  readily  decomposed  mio  Hydradinine  (CH2O2C9H7NCH3) 
and  opianic  acid.  Chemically  hydrastine  is  nearly  related  to  Narcotine  (C22H23- 
NO7),  one  of  the  opium  alkaloids,  which  differs  from  it  only  in  the  possession 
of  another  methoxyl  group;  and  narcotine  can  also  be  decomposed  into  Cotarnine 
(C12H15  NO4)  and  opianic  acid,  cotarnine  differing  from  hydrastinine  again  only 
by  a  methoxyl.  Another  opium  alkaloid,  Laudanosine,  undergoes  a  similar  decom- 
position and  the  resulting  alkaloid  has  been  shown  by  Laidlaw  to  reseniblc 
hydrastinine  in  action.  The  effects  of  the  three  original  alkaloids,  hydrastine, 
narcotine,  and  laudanosine  in  the  body  also  present  many  similarities. 

Action. — Hydrastine  causes  in  frogs  an  increase  in  the  reflex  irritability  and 
eventually  tetanus  exactly  resembling  that  produced  by  strychnine,  and  like 
it  terminating  finally  in  paralysis. 

In  mannnals  the  pulse  is  slowed  by  comparatively  small  quantities,  while 
somewhat  larger  doses  cause  general  feebleness,  tremor,  dyspnoea,  and  inco- 
ordination in  the  movements.  Very  large  quantities  elicit  clonic  and  then  tonic 
convulsions  and  tetanus,  during  which  the  respiration  ceases.  The  pulse  is 
slowed  at  first  from  stimulation  of  the  vagus  centre,  is  afterward  (juickoned 
from  its  paralysis,  and  still  later  becomes  slow  again  from  direct  action  on  the 
25 


386  SUBSTANCES  ACTING  AFTER  ABSORPTION 

cardiac  muscle.  The  blood-pressure  rises  from  constriction  of  the  arterioles 
but  afterward  falls  from  the  weakness  of  the  heart;  the  constriction  of  the 
arterioles  is  due  to  stimulation  of  the  vasomotor  centre  in  the  medulla.  Hydras- 
tine  injected  intravenously  arouses  the  uterus  to  contractions,  which  are  some- 
times rhythmic  in  character,  hut  sometimes  assume  a  prolonged  tetanic  form; 
the  action  is  a  local  one,  for  it  also  occurs  in  the  excised  organ.  Hydrastine  is 
excreted  as  such  in  the  urine.  When  it  is  administered  for  some  time,  a  cumu- 
lative action  is  said  to  be  developed. 

Canadine  in  small  ([uantities  produces  depression  and  drowsiness  followed 
by  complete  recovery  without  further  symptoms.  In  larger  quantities  v. 
Bunge  found  that  it  caused  a  short  stage  of  excitement,  which  was  followed 
b}^  depression  and  paratysis  of  the  central  nervous  system.  It  has  little  or 
no  effects  on  the  mammalian  circulation  when  administered  in  ordinary  doses, 
but  very  large  quantities  cause  weakness  and  arrhythmia  of  the  heart.  Its 
injection  is  followed  by  violent  peristalsis  of  the  intestine  and  diarrhoea. 
Canadine  is  present  in  only  very  small  quantity  in  the  Golden  Seal  and  has 
apparently  little  importance  in  therapeutics. 

Hydrastinine  differs  from  hydrastine  in  causing  no  marked  disturbance  of 
the  centres  of  motion  and  feeling  save  in  enormous  doses,  which  paralyze  the 
nervous  sj^stem.  The  heart  is  slowed  and  strengthened  by  small  doses,  appar- 
ently from  direct  action  on  the  muscle,  and  the  output  is  increased.  This  causes 
a  small  rise  in  the  blood-pressure,  and  another  factor  leading  to  the  same  result 
is  a  slight  constriction  of  the  arterioles  through  a  direct  action  on  the  muscular 
coats;  this  slight  constriction  is  observed  also  on  perfusing  the  surviving 
organs.  The  action  on  the  blood-pressure  is  not  very  marked,  however,  even 
when  large  doses  are  employed. 

The  most  important  action  of  hydrastinine  is  that  on  the  uterus,  which 
increases  greatly  in  tone  and  often  contracts  rhythmically  and  powerfully 
under  its  influence.  This  occurs  also  in  the  excised  organ  and  is  due  to  a  direct 
action  on  the  uterine  muscle.  There  is  apparently  another  effect  due  to  stimu- 
lation of  the  ganglia  on  the  fibres  of  the  hypogastric  nerves  supplying  the 
uterus,  for  in  the  non-pregnant  cat,  Laidlaw  observed  an  inhibition  of  the 
organ  from  hydrastinine  which  could  be  removed  b}'  large  doses  of  nicotine. 
This  nervous  action  is  not  of  imjiortance,  however,  in  the  pregnant  uterus  in 
which  hydrastinine  is  used  chiefly,  and  in  fact  would  here  reinforce  the  direct 
muscular  effect.  Archangelsky  states  that  a  10  per  cent,  solution  of  hydras- 
tinine applied  locally  causes  dilatation  of  the  pujiil,  which  reaches  its  maximum 
in  two  to  three  hours,  and  lasts  for  twelve  to  fifteen  hours. 

Cotarnine  differs  from  hydrastinine  in  not  constricting  the  vessels  or  strengtli- 
ening  the  lieart,  so  that  the  blood-pressure  falls  under  it.  The  action  on  the 
uterus  also  seems  rather  weaker.  The  base  obtained  from  laudanosine  resembles 
hydrastinine  exactly  in  action. 

Preparations. 

Hydrastis  (U.  S.  P.),  Hydrastis  Rhizoma  (B.  P.),  the  rhizonu'  and  I'oots  of 
llvdrastis  Canadensis,  Golden  Seal,  containing  2.5  per  cent,  of  hvdrastine 
(U.  S.  P.). 

Fluidcxtraciuni  Jlydnistis  (U.  8.  P.)  (2  percent.),  2  c.c.  (30  mins.). 

Kxtrdctum  IlTjdrdstis  Liquidum  (B.  P.),  5-15  mins. 

Glycerilum.  Hydrastis  (U.  8.  P.),  2  c.c.  (30  mins.). 

Tinclum  Iliidmstis  (U.  8.  P.,  B.  P.)  (0.4  i^er  cent.  (U.  8.  P.)  ),  4  c.c.  (60  mins.); 
B.  P.  ^-1  fl.dr. 

Ilydrdstiitd  (V.  8.  P.).  wliilc,  hitter,  almost  insohiMc  crvstals.  10  nigs. 
i\gv.). 

Ilydrdstnitiuv  H ydrorldonilKiii  (I  .  8.  P.),  0.03  G.  (',  gr.),  gi\en  in  .solutioi\ 
hypodcrniically  or  !»y  the  mouth,  or  in  pills  or  tal)let.s. 

Cotarnine   has  been   introduceil   under   the   name  of  Styptirliu    anil  Styjitol 


THE  NITRITES  387 

as  a  substitute  for  hydrastiuine  in  uterine  hemorrhage.     Dose,  0.02-0.03  G. 

(Wgr.). 

Therapeutic  Uses. — Hydrastis  has  been  used  as  a  stomachic  bitter  and  the 
hirge  quantity  of  l^crberine  contained  in  it  would  seem  to  give  it  a  place 
along  with  the  simple  bitters.  It  has  also  been  credited  with  some  obscure 
action  on  the  mucous  membranes  when  locally  applied,  through  which  it  is 
said  to  benefit  manj'  forms  of  catarrhal  inflammation;  for  this  purpose  the 
glycerite  may  be  used.  Besides  various  conditions  in  which  its  use  was  attended 
by  doubtful  success,  it  has  been  used  in  haemorrhage  from  the  uterus;  but  for 
this  purpose  hydrastiuine  ought  to  be  preferred,  as  it  acts  more  strongly  on  the 
uterus  than  h_ydrastine.  The  conditions  in  which  it  is  indicated  seem  to  be 
moderate  hsemorrhage;  for  example,  hydrastiuine  is  of  value  in  excessive 
menstrual  flow,  while  in  post-partum  haemorrhage  it  seems  to  have  little  effect. 
Hj^drastine  and  hj'drastinine  have  not  attained  any  assured  position  in  thera- 
peutics, for  at  best  thej'  can  only  be  considered  inferior  substitutes  for  ergot, 
which  has  a  much  more  decided  action  on  the  vessels  and  the  uterus.  Cotarnine 
is  inferior  to  hydrastiuine  and  might  be  dismissed. 

Bibliography. 

p.  Marfori.  Arch.  f.  exp.  Path.  u.  Pharm.,  xxvii.,  p.  161.  Arch.  ital.  de  Biol., 
xxviii.,  p.  191. 

E.  Falk.     Yiichow's  Arch.,  cxix.,  p.  399;    cxlii.,  p.  360. 

Cerna.     Therap.  Gaz.,  1891,  pp.  289,  361. 

K.  V.  Bunge.     Arbeiten  a.  d.  pharmakolog.  Institut.  Dorpat,  xi.  and  xii.,  p.   119. 

Fellner.     Ccntralbl.  f.  Physiol.,  xi.,  p.  374. 

Santesson.     Skandin.  Arch.  f.  Physiologie,  vi.,  p.  308. 

Laidlaw.    Biochemical  Journal,  v,  p.  243. 


XIX.     THE  NITRITES. 

The  nitrites  have  a  powerful  action  on  the  arteries,  which  they  cause 
to  dilate  by  depressing  the  muscle  of  the  walls. 

Those  which  have  been  examined  more  carefully  are  the  Nitrite  of 
Sodium  and  the  Nitrous  Esters  of  the  methane  series,  especially  the 
Nitrite  of  Amyl,  w^hich  is  largely  used  in  therapeutics.  In  these  com- 
pounds the  radicle  — NO  is  attached  to  the  metal  or  alkyl.  through 
an  atom  of  oxygen,  the  formula?  being  Na — O — NO,  CH3 — O— NO, 
C3H7— O — NO,  CsHu — O — NO,  etc.,  and  the  chief  constituent  is 
the  O — NO,  the  metal  or  radicle  being  of  less  importance.  A  closely 
allied  series  of  bodies  are  the  nitrates,  in  which  the  nitrogen  has  five 
valencies  and  is  connected  again  to  the  metal  or  radicle  bv  oxvgen, 
Na— O— NO2,  CH3— O— NO2,  CsHn— O— NO2,  etc.  The'  metallic 
nitrates  differ  entirely  from  the  nitrites  in  their  effects  and  are  used 
as  diuretics  (p.  292).  Some  of  the  Nitric  Esters,  however,  undergo 
reduction  when  brought  into  contact  with  organic  matter,  and  nitrites 
are  thus  formed,  so  that  these  bodies  have  effects  very  similar  to  those 
of  the  true  nitrites,  and  have  to  be  discussed  along  with  them.  The 
best  known  of  such  nitrates  is  the  so-called  Nitroqli/ccrin,  which  is 
really  the  trinitrate  of  glycerin,  (CH2(ON02)CH(ONa)CHo(ONOo)), 
and  is  broken  up  by  alkalies  into  a  mixture  of  nitrates  and  nitrites. 
The  nitrates  have  practically  no  action  in  the  small  quantities  given, 
so  that  almost  all  the  efl'ects  of  nitroglvcerin  are  due  to  the  nitrite 


388  SUBSTANCES  ACTING  AFTER  ABSORPTION 

formed.    Many  other  organic  nitrates  also  form  nitrites  in  the  tissues, 
but  none  of  them  with  such  rapidity  as  nitroglycerin. 

Two  which  have  been  used  to  some  extent  in  the  last  few  j^ears  are  solids 
— Erythrol  Tetrmiitrate,  and  Mannitol  Hexanitrate.  They  act  much  more  slowly 
and  for  a  longer  time  than  nitroglycerin. 

Another  series  of  bodies  which  may  be  mentioned  as  occasionally  acting 
like  nitrites,  although  more  feebly,  are  the  nitro-bodies.  In  these  the  nitrogen 
is  attached  to  the  alkyl  directly,  and  not  through  the  intervention  of  an  oxygen 
atom.  Examples  of  these  are  Nitromethane,  H3C — XO2,  and  Nitroethane, 
CH3 — CH2 — NO2.  Their  action  is  so  feeble  as  to  preclude  their  use  in  thera- 
peutics, and  seems  due  to  the  — NO2  being  split  off  in  the  tissues. 

The  best  known  member  of  the  group  is  Amyl  Nitrite,  and  its  action 
will  first  be  described,  while  the  points  in  which  tlie  effects  of  the 
other  members  diverge  from  it  will  be  discussed  later. 

Symptoms. — After  the  inhalation  of  a  few  drops  of  amyl  nitrite,  the 
face  becomes  flushed,  and  the  patient  complains  of  a  feeling  of  fulness 
and  throbbing  in  the  head.     Some  headache  and  confusion  is  often 

Fig.  40 


A  R         ^  C 

Tracing  of  the  blood-pressure  in  the  rabbit  under  amyl  nitrite.  From  A  to  B,  the 
blood-pressure  is  the  normal.  At  B  the  inhalation  was  begun  and  the  disturbance  of  the 
respiration  is  reflected  in  the  blood-presuro  tracing.  Immediately  afterwards  the  blood- 
pressure  begins  to  fall  and  continues  to  do  so  even  after  the  inhalation  ceased  at  C.  Note 
that  the  rhythm  and  strength  of  the  pulse  are  comparatively  little  altered. 

present,  the  pulse  is  accelerated,  and  the  respiration  is  sonu'what 
quicker  and  deeper.  The  flush  is  often  confined  to  the  face  and  neck, 
but  sometimes  spreads  over  the  whole  trunk,  and  passes  oft'  in  a  few 
minutes,  unless  the  inhalation  is  continued.  If  large  quanitites  of 
the  drug  be  inhaled  at  once,  however,  or  if  the  inhalation  be  continued 
for  some  time,  a  feeling  of  giddiness,  weakness  and  eventually  stujwr 
follow,  the  pulse  becomes  slow,  while  the  respiration  still  remains 
accelerated  but  is  shallower  and  often  somewhat  irregular;  convulsive 
movements  may  occur,  but  in  general  large  quantities  may  be  taken 
without  actual  danger  in  the  human  subject.  The  blood  is  said  to  have 
assunu'd  a  dark  color  in  some  cases,  but  this  seems  to  be  rare. 

Action:  Circulation.  -The  flushing  and  dilatation  of  the  arterioles  of 
the  head  is  found  to  b(>  accompanied  and  followed  by  a  profound  fall 
in  tlie  blood-pressure  iu  uiau  and  animals.  The  heart  is  acceliTated 
at  the  same  time,  and  therefore  is  not  respousibl(>  for  the  change.  The 
cause,  as  has  been  repeatedly  demonstrated,  is  the  dilatation  of  the 


THE  NITRITES  389 

peripheral  vessels,  both  arterioles  and  veins  widenin<i;  very  consi(lcra})ly 
under  the  influence  of  the  drug;  the  vessels  of  the  abdominal  organs 
and  the  face  are  more  affected  than  those  of  the  extremities.  The 
vasomotor  centre  is  not  concerned  in  the  widening  of  the  vessels,  for 
if  amyl  nitrite  is  allowed  to  pass  through  the  medulla  without  reaching 
the  peripheral  vessels,  no  fall  of  pressure  occurs.  And  stimulation  of  a 
constrictor  nerve  such  as  the  splanchnic  still  produces  some  rise  in  the 
blood-pressure,  so  that  the  nerve  terminations  seem  to  be  intact.  The 
seat  of  action  of  amyl  nitrite  is  therefore  the  unstriated  muscle  of  the 
arteries  and  veins.  No  satisfactory  explanation  has  been  offered  for 
the  fact  that  in  the  skin  only  the  vessels  of  the  head  and  neck  should 
be  dilated,  but  other  facts  seem  to  indicate  that  these  vessels  occupy  an 
exceptional  position  as  regards  their  innervation  and  their  reactions  to 
drugs.  Darwin  was  the  first  to  point  out  that  the  blush  of  amyl 
nitrite  corresponds  in  extent  with  the  blush  produced  by  emotion. 
This  blush  effect  seems  due  to  the  amyl  in  part,  for  other  amyl  esters 
induce  it,  though  none  to  the  same  extent  as  the  nitrite.  The  direct 
action  on  the  vessel  walls  may  be  easily  shown  by  passing  blood  into 
the  artery  of  the  amputated  extremity  of  an  animal,  and  measuring 
the  amount  coming  from  the  veins.  If  a  few  drops  of  amyl  nitrite 
be  added  to  the  perfused  blood,  the  outflow  from  the  vein  is  greatly 
increased,  although  here  no  nervous  mechanism  can  be  concerned. 

The  acceleration  of  the  pulse  is  more  marked  in  man  and  the  dog 
than  in  other  animals,  and  is  the  result  of  the  fall  in  blood-pressure 
which  induces  anaemia  of  the  brain  and  thus  depresses  the  tone  of  the 
inhibitory  cardiac  centre  and  probably  excites  the  accelerator  apparatus. 
The  coronary  arteries  of  the  heart  are  dilated  along  with  those  of  other 
parts  of  the  body. 

Large  quantities  of  amyl  nitrite  slow  and  weaken  the  contractions 
of  the  heart,  owing  to  a  direct  depressing  action  on  the  muscle.  In 
the  frog,  the  heart  is  usually  slowed  from  the  beginning  of  the  applica- 
tion. 

The  Respiration  is  generally  accelerated,  and  at  the  same  time  ren- 
dered deeper  by  amyl  nitrite.  Not  infrequently  the  breath  is  held  at 
first,  owning  to  a  reflex  from  the  nasal  mucous  membrane,  but  this  is 
not  so  marked  as  in  the  inhalation  of  more  irritant  vapors,  such  as 
chloroform  or  ether.  The  acceleration  is  the  result  of  the  fall  in  pressure 
lessening  the  supply  of  blood  to  the  brain  and  arousing  the  respiratory 
centre.  After  long  inhalation  the  respiration  becomes  slower  and 
shallower  and  in  animals  death  occurs  from  asphyxia.  The  walls  of  the 
pulmonary  vessels  are  less  affected  by  the  nitrites  than  those  of  the 
systemic  circulation.  The  bronchial  muscle  is  apparently  relaxed  by 
the  inhalation  of  amyl  nitrite  or  by  the  administration  of  other  members 
of  the  group  by  the  stomach,  for  relief  is  given  in  asthma.  An  old 
method  of  inducing  this  effect  is  by  burning  paper  impregnated  with 
saltpeter  and  inhaling  the  fumes,  which  contain  nitrite  formed  by  the 
reduction  of  the  nitrate. 

The  Kidneys  are  not  much  affected  by  this  series;  occasional! v  a 


390 


SUBSTANCES  ACTING  AFTER  ABSORPTION 


Fig.  41 


w.-'.iiiltKii.ftw^ 


slio^lit  iiKToasc  in  the  urine  is  observed,  at  other  times  a  decrease,  and 
after  lar^e  (juantities  anuria  may  occur.  These  effects  are  evidently 
(hie  to  the  chan<i;es  in  the  caHhre  of  the  renal  vessels.  A  small  quantity 
may  widen  them  when  they  are  too  contracted  to  allow  of  the  maximal 
secretion,  while  on  the  other  hand,  if  the  normal  calibre  is  the  optimal, 
a  nitrite  may  lessen  the  secretion  by  lowering  the  general  blood-pressure. 
When  large  quantities  lower  the  i)ressure,  they  inevitably  lead  to  a 
lessened  secretion  or  anuria. 

Small  quantities  of  amyl  nitrite  seem  to  have  no  action  whatsoever 
on  the  higher  parts  of  the  Central  Nervous  System.  The  throbbing  in 
the  head  and  slight  confusion  are  e^'idently 
due  to  the  fall  in  general  blood-pressure.  The 
sight  is  curiously  affected  in  some  people,  for 
when  a  dark  object  on  a  white  background  is 
looked  at,  it  seems  surrounded  by  a  yellow 
ring  and  that  again  by  a  blue  one.  In  the 
beginning  the  medullary  centres  may  be  slightly 
acted  on  reflexly  from  irritation  of  the  nasal 
sensory  terminations,  and  later  the  fall  in 
blood-pressure  and  consequent  anaemia  of  the 
medulla  lowers  the  activity  of  the  inhibitory 
centre  for  the  heart  and  stimulates  the  respir- 
atory centre.  The  spinal  cord  is  not  acted  on 
in  mammals,  but  is  depressed  in  the  frog. 

After  large  quantities  convulsions  are  often 
observed;  these  seem  to  be  of  cerebral  origin, 
and  are  probably  due  to  the  circulatory  changes 
and  the  formation  of  methcemoglobin. 

The  Peripheral  Nerves  and  the  Muscles  are 
unaffected  by  the  inhalation  of  amyl  nitrite, 
but  when  the  frog's  muscles  are  exposed  to 
the  direct  action  of  the  vapor,  they  undergo  a 
slow,  passive  shortening  and  rigor,  and  on 
periodical  stimulation  the  contractions  become 
rapidly  weaker,  until  finally  no  response  is 
made  to  the  electric  shock.  Involuntary 
muscle  is  more  easily  affected  than  striated 
fibres,  as  has  been  shown  by  the  behavior  of  the  intestine  and  ureters,  but 
even  these  seem  less  readily  ])aralyzed  than  the  nuiscle  of  the  vessel  walls, 
the  depression  and  paralysis  of  which  lead  to  the  fall  in  the  arterial 
tension,  as  has  been  already  stated.  The  nerve  terminations  seem  to 
he  unaffected  even  by  very  large  quantities,  so  that  as  long  as  a  con- 
traction of  the  nmscles  can  be  elicited  by  direct  stinuilation,  it  follows 
also  on  stimulation  of  the  motor  nerve,  and  the  ^'agus  terminations  in 
the  heart  can  transmit  impulses  as  long  as  the  heart  continues  to  beat. 
The  Temperature  is  somewhat  lowered  by  the  nitrite  series,  owing  to 
tlie  dilatation  of  the  skin  vcssc^ls,  but  this  fall  is  insignificant, 

Ani\l   nitrite  causes  the  Blood  to  assume  a  dark   chocolate   color. 


Blood-prcssure  under 
amyl  nitrite  taken  on  a  very 
slow  drum  in  order  to  de- 
monstrate the  recovery. 
The  whole  tracing  occupied 
some  six  minutes.  The 
rapid  fall  of  pressure  is 
followed  by  an  almost 
equally  rapid  return  to 
normal.  (Cash  and  Dun- 
stan.) 


THE  NITRITES 


391 


both  in  the  body  and  in  the  test-tube.  The  color  is  due,  not  to  any 
conii)()und  formed  by  the  nitrites,  but  to  their  chanjjing  the  luemo- 
fijlobin  to  niethtemoglobin  and  nitric-oxide-haunoglobin  compounds. 
The  change  in  the  htemoglobin  does  not  entail  the  destruction  of  the 
red  corpuscles,  and  the  compounds  are  eventually  reduced  by  the  tissues, 
although  the  reduction  progresses  much  more  slowly  than  that  of  ordi- 
nary oxyha^moglobin.  In  man,  usually  very  little  of  the  haemoglobin 
is  thus  transformed,  and  even  after  large  quantities  have  been  inhaled 
no  abnormal  coloration  of  the  blood  is  noticeable,  but  it  has  been 
demonstrated  recently  that  the  alteration  of  the  haemoglobin  is  the 
cause  of  death  in  some  animals,  through  the  blood  becoming  incapable 
of  carrying  oxygen  to  the  tissues.  If,  however,  asphyxia  be  prevented 
by  the  inhalation  of  oxygen  under  pressure,  the  tissues  themselves  are 
eventually  acted  on.  The  formation  of  methsemoglobin  does  not  seem  to 
bear  any  relation  to  the  action  of  the  nitrites  on  the  vessel  walls  and 
is  identical  with  that  caused  by  other  reducing  bodies,  which  have  no 
action  on  the  bloodvessels. 

Excretion. — After  absorption  into  the  blood,  amyl  nitrite  seems  to 
break  up  with  the  formation  of  nitrites  of  the  alkalies.  These  undergo 
partial  oxidation  and  appear  in  the  urine  in  the  form  of  nitrates  and 
nitrites,  but  the  quantity  of  these  excreted  is  never  equal  to  the  nitrite 
absorbed,  so  that  it  seems  probable  that  some  part  undergoes  still 
further  change.  The  amyl  disappears,  and  is  probably  oxidized  com- 
pletely, although  some  may  appear  in  the  breath. 


Fig.  42 


2K  hrs. 


Diagram  to  illustrate  the  intensity  and  duration  of  the  action  of  the  members  of  the 
nitrite  series.  The  extent  of  the  fall  of  pressure  is  measured  along  the  vertical,  the  dura- 
tion along  the  horizontal  line.  A,  amyl  nitrite,  ethyl  nitrite,  etc.;  B,  nitroglycerin; 
C,  sodium  nitrite;  D,  erythrol  tetranitrate.  The  greatest  fall  in  pressure  occurs  in  A, 
but  it  passes  off  for  the  most  part  in  five  minutes  and  entirely  in  twenty.  Nitroglycerin 
acts  more  rapidly  than  the  last  two,  and  its  effects  continue  almost  as  long  as  those  of 
sodium  nitrite.  Erythrol  tetranitrate  only  exerts  its  full  effect  after  the  action  of  the 
others  has  passed  off.     (After  Bradbury.) 


Nitrite  of  amyl  given  by  the  stomach  is  very  much  less  active  than 
when  inhaled,  as  the  nitrous  acid  is  freed  by  the  gastric  juice  and 
immediately  decomposed.  When  injected  subcutaneously  it  acts  much 
more  slowly  and  weakly  than  when  absorbed  by  the  lungs,  and  gen- 
erally gives  rise  to  glycosuria  and  slight  diuresis.  No  satisfactory 
explanation  of  this  fact  has  been  given,  but  it  is  possible  that  the 
formation  of  methoemoglobin  may  cause  partial  asphyxiation  of  ti:e 


302  SUBSTANCES  ACT  I  NO  AFTER  ABSORPTION 

tissues,  and  thus  cause  the  formation  of  excess  of  lactic  acid  and 
fi'lycosuria. 

The  pharniacopaMal  aniyl  nitrite,  is  a  mixture  of  the  nitrites  of  amy!, 
butyl,  i)roi)yl,  and  ethyl.  The  i)ure  nitrites  of  this  series  resemble  each 
other  closely  in  <i;eneral  features;  the  more  unsta})le  the  compound,  the 
more  rapidly  does  the  fall  in  blood-pressure  occur,  while  the  less  easily 
decomposed  compounds  are  somewhat  slower  in  their  action,  but  cause 
dei)ressi()n  of  the  blood-pressure  for  a  longer  time. 

Sodium  Nitrite  resembles  the  organic  nitrites  closely  in  action.  It 
is  administered  by  the  stomach,  and  therefore  acts  more  slowly  than 
amyl  nitrite,  but  its  effects  last  much  longer.  The  gastric  juice  liberates 
part  of  the  nitrous  acid  before  absorption  can  occur,  and  it  is  immedi- 
ately decomposed  and  often  causes  some  eructation  and  may  also 
give  rise  to  irritation  of  the  gastro-intestinal  mucous  membrane.  The 
nitrite  absorbed  is  excreted  as  nitrate  in  the  urine,  although  some  of 
it  may  remain  unoxidized.  The  metallic  nitrites  do  not  as  a  rule  cause 
so  much  headache  and  flushing  of  the  face  and  neck  as  the  alkyl  com- 
pounds. 

Nitroglycerin  produces  the  same  effects  as  the  other  members  of 
this  series,  but  acts  much  more  powerfully  than  either  the  metallic  or 
alkyl  nitrites.  It  presents  some  minor  points  of  difference,  as  in 
causing  more  severe  headache  in  man.  It  is  not  decomposed  in  the 
stomach,  })ut  on  reaching  the  blood,  at  once  breaks  up  into  glycerin, 
nitrites  and  nitrates.  Its  action  commences  very  soon  after  its  admin- 
istration, and  lasts  much  longer  than  that  of  amyl  nitrite.  The  explana- 
tion of  its  greater  activity  may  be  that  it  is  absorbed  unchanged,  but 
is  then  broken  up  at  once,  while  the  metallic  nitrites  are  decomposed  in 
the  stomach  and  much  of  the  nitrous  acid  is  lost.  Nitroglycerin  is  not 
wholly  broken  up  in  the  human  body,  however,  for  it  has  been  found 
in  the  urine,  and  the  headache  which  so  frequently  follows  its  admin- 
istration in  man  has  been  ascribed  to  the  undecomposed  molecule,  and 
not  to  the  nitrite  constituent.  It  is  generally  supposed  to  be  extremely 
poisonous,  and  is  prescribed  in  minute  doses,  but  it  has  been  shown 
that  while  very  small  quantities  are  sufficient  to  produce  therapeutic 
effects  in  man,  the  toxic  dose  is  enormous  in  animals. 

Several  other  organic  nitrates  have  also  been  found  to  reduce  the 
blood-pressure,  and  to  cause  the  formation  of  metluemoglobin.  but 
their  decomposition  proceeds  much  more  slowly  than  that  of  nitro- 
glycerin and  they  have  not  been  much  used  in  therapeutics.  Erythrol 
tetranitrate  and  mannitol  hexanitrate  act  more  slowly,  and  the  fall  of 
pressure  is  more  gradual,  and  lasts  longer  than  under  any  others  of 
the  series. 

Preparations. 

Amyl  Nithis  (H.  P.),  Amylis  Nitris  (U.  S.  P.),  ii  yellow,  very  volatile 
fluid,  with  a  stroiiji.  fruity  odor,  soluble  in  alcohol  and  ether  but  rapidly  do- 
coiiiposed  l)y  water.  It  consists  of  the  nitrite  of  isoaniyl  for  the  most  part, 
along  with  sinall  quantities  of  the  nitrites  of  butyl,  propyl,  etc.  2-5  niins.  :uv 
i    'ured  on  a  handkerchief  and  inhaled.    A  convenient  preparation  is  \\\v  amyl 


THE  NITRITES 


m 


nitrite  "pearls,"  which  arc  thin  glass  capsules,  each  containing  a  close  of  the 
remedy,  and  one  of  which  is  broken  in  the  handkerchief  when  necessary. 
Amyl  nitrite  is  liable  to  decompose  when  kept  long,  and  ought  to  he  used  only 
when  recently  prepared.    0.2  c.c.  (3  mins.). 

Spiritus  Glycerylis  Nitratis  (U.  8.  P.),  Liquor  Trinitrini  (B.  P.),  is 
a  1  per  cent,  alcohohc  solution  of  nitroglycerin.  0.05  c.c.  (1  min.);  B.  P.,  |-2 
mins. 

Tabell^  Trinitrini  (B.  P.),  or  nitroglycerin  tablets,  are  formed  of  choco- 
late and  contain  each  ylo  gr.  of  nitroglycerin.    1-2  tablets. 

SoDii  NiTRis  (U.  S.  P.,  B.  P.)  (NaNOo),  0.065  G.  (1  gr.);  B.  P.,  i-2  grs., 
in  tablets  or  in  solution. 

Spirihis  Athens  Nitrosi  (U.  S.  P.,  B.  P.),  sweet  spirit  of  nitre,  contains 
2-4  per  cent,  of  ethyl  nitrite,  along  with  ether  and  aldehyde  in  alcoholic  solution. 
When  freshly  prepared  it  acts  like  the  other  nitrites,  but  when  prescribed  along 
with  water,  as  is  usually  the  case,  the  nitrite  escapes  rapidlj^,  and  it  has  httle 
effect  except  from  the  ether  and  alcohol.    2  c.c.  (30  mins.) :  B.  P.,  15-60  mins. 

Erythrol  tetranitrate  (CH20N02(CHON02)2CH20N02)  is  a  solid,  and  is 
recommended  in  doses  of  0.05  G.  (1  gr.),  in  pills,  tablets  or  alcoholic  solution. 
Like  nitroglycerin,  it  is  a  dangerous  explosive,  and  one  fatality  has  already 
occurred  in  forming  it  into  pharmaceutical  preparations. 


Fig.  43 


f"*"   11  iiiiiiiiiiii 


-•  •  I  I  I  I  I  I  r  T  1 


Pulse  tracing  in  case  of  angina  pectoris;    a,  before;    b,  during 

nitrite. 


the  inhalation  of  amyl 


Therapeutic  Uses.— The  nitrites  were  introduced  into  therapeutics 
by  Brunton,  who  advised  their  use  in  angina  pectoris  to  reheve  spasm 
of  the  arteries.  Some  question  has  arisen  as  to  whether  angina  pectoris 
is  generally  accompanied  by  high  arterial  tension,  and  amyl  nitrite 
often  gives  relief  in  cases  in  which  the  blood-pressure  does  not  seem 
abnormal,  so  that  the  mechanism  of  its  action  is  not  completely  deter- 
mined. For  rapid  transient  effects  nitrite  of  amyl  seems  specially 
indicated,  while  nitroglycerin  and  nitrite  of  sodium  are  more  suited 
to  produce  a  depression  of  some  duration.  Thus  during  the  attack 
of  angina  pectoris,  amyl  nitrite  is  often  found  to  give  instant  relief, 
but  if  nitrite  of  sodium  or  nitroglycerin  is  administered  every  4-6 
hours,  no  attack  may  occur.  The  disadvantage  of  the  metallic  nitrites 
is  the  frequent  eructation  they  produce,  while  nitroglycerin  often  causes 
severe  headache,  which,  however,  disappears  in  some  cases  after  repeated 
use.  The  pulse  assumes  the  dicrotic  character  under  all  of  the  nitrite 
series,  owing  to  the  reduced  peripheral  resistance  (Fig.  43). 


394 


SUBSTANCES  ACTING  AFTER  ABSORPTION 


Besides  in  aii,s2;iiia  pectoris,  the  nitrite  series  may  be  used  in  any  con- 
dition in  which  it  is  supposed  that  the  arterial  tension  may  be  lowered 
witli  benefit  to  the  economy.  Thus  nitrofj;lycerin  has  been  advised 
in  heart  disease  and  has  accordingly  been  placed  by  some  among  the 
heterogeneous  group  of  "Cardiac  tonics  or  stimulants."  Its  bene- 
ficial effects  are  not  due  to  any  direct  action  on  the  heart,  but  to  its 
decreasing  the  resistance  against  which  the  systole  is  performed.  In 
this  w^ay  the  contraction  of  the  ventricle  is  rendered  more  complete, 
and  the  output  of  the  heart  may  be  increased.  In  weak  hearts  strug- 
gling against  a  high  aortic  resistance,  this  relief  may  be  followed  by 
marked  benefit,  and  for  this  reason  nitrite  preparations  (nitroglycerin) 


Fig.  44 


1 

A 

2 ' 

- 

A 

i 

/ 

T 

/ 

^ 

^ 

' 

1 

^ 

-n 

' 

' 

; 

1 

1 

Va 

I 

I 

I 

' 

j 

1 

1      i 

1      1 

r"  "i  i" 

/ 

i 

/ 

' 

f^ 

/ 

/ 

^ 

/ 

^ 

1 

J 

I 

5 

( 

- 

f 

f 

I 

0 

11    1 

2   13 

1 

4 

1 

5 

1 

6 

1 

7 

18 

Blood-pressure  chart  during  an  attack  of  angina  pectoris.  The  pressure,  originally 
140  to  150  mm.  of  mercury,  rapidly  rose  to  220,  and  intense  pain  was  present  over  the  heart. 
At  A  and  A,  amyl  nitrite  was  inhaled  and  the  pressure  fell  to  105  mm.  At  P  the  pain 
had  disappeared.  The  pressure  rose  again  rapidly  and  at  S  the  pain  recurred  slightly 
and  was  very  severe  at  R.     Time  in  minutes. 


are  often  prescribed  in  chronic  Bright's  disease.  Amyl  nitrite  has  been 
advised  in  accidents  during  chloroform  auirsthesia  on  the  theory  that 
it  would  benefit  the  circulation;  but,  as  a  matter  of  fact,  it  would  appear 
strongly  contra-indicated,  in  these  cases,  in  which  it  is  true  that  the 
heart  is  extremely  dej)ressed,  but  in  which  the  arterial  tension  is  prac- 
tically zero.  Its  use  is  especially  irrational  if,  as  has  been  suggested, 
the  failure  of  tiie  rcsi)iration  is  partly  due  to  amemia  of  the  central 
nervous  system.  The  cases  in  which  recovery  has  occurred  after  this 
measure  may,  in  fact,  be  said  to  have  recovered,  not  owing  to,  but  in 
spite  of  the  use  of  amyl  nitrite. 

Amyl   nitrite   has   been   suggested    in   internal   Iwcniorrhagc,   on   the 


THE  DIGITALIS  SERIES  395 

view  that  by  reducing  the  pressure  in  the  interior  of  the  vessels  it 
would  permit  a  clot  to  form  at  the  point  of  injury.  On  the  other 
hand,  the  dilatation  of  the  abdominal  vessels  may  lead  to  aniemia  of 
the  brain  and  syncope,  and  this  has  prevented  the  use  of  the  drug  in 
practice,  except  in  unusual  conditions. 

In  very  advanced  degeneration  of  the  cardiac  muscle  fibre,  the 
administration  of  amyl  nitrite  is  distinctly  contra-indicated,  for  the 
blood-pressure  is  low  and  any  further  reduction  may  lead  to  syncope 
from  an.emia  of  the  brain,  and  to  still  greater  weakness  of  the  heart 
from  the  low  pressure  in  the  coronary  arteries  lessening  its  nutrition. 

Nitrite  of  amyl  has  been  used  largely  in  asthma  and  in  cardiac 
dyspnoea.  Its  action  is  often  beneficial  and  has  been  attributed  to  its 
depressing  the  bronchial  muscles,  which  are  supposed  to  be  in  a  con- 
dition of  spasmodic  contraction  in  asthma.  In  the  cardiac  cases  its 
action  in  removing  the  dyspnoea  may  be  due  to  its  lowering  the  pres- 
sure in  the  systemic  arteries  and  thus  relieving  the  heart. 

In  some  cases  of  headache,  nitrite  of  amyl  is  of  marked  benefit, 
while  in  others  it  aggravates  the  condition.  This  is  perfectly  intelli- 
gible, as  some  forms  of  headache  may  be  due  to  cerebral  congestion 
and  peripheral  constriction,  while  others  arise  from  anaemia  of  the 
brain. 

Bibliography. 

Brunton.     Journ.  of  Anat.  and  Phys.,  v,  p.  92. 

Atkinson.     Journ.  of  Anat.  u.  Phys.,  xxii,  p.  225. 

Mayer  u.  Friedrich.     Arch.  f.  exp.  Path.  u.  Pharm.,  v,  p.  55. 

Hay.     Practitioner,  xxx,  pp.  179-321. 

Leech.     British  Medical  Journal,  1893,  i,  p.  1305  and  ii,  p.  4. 

Cash  and  Dunstan.     Phil.  Trans,  of  the  Royal  Soc,  clxxxiv,  B,  p.  505. 

Gamgee.     Ibid.,  clviii,  p.  589. 

Mitchell  and  Reichert.     Amer.  Journ.  of  the  Medical  Sciences,  Ixxx,  p.  158. 

Haldane,  Makgill,  and  Mavrogordato.     Journal  of  Physiology,  xxi,  p.  160. 

Schadow.     Arch.  f.  exp.  Path.  u.  Pharm.,  vi,  p.  194. 

Filehne.     Arch.  f.  Anat.  u.  Phys.,  1879,  p.  385. 

Marshall.     Journ.  of  Phys.,  xxii,  p.  1. 

Bradbury.     Brit.  Med.  Journ.,  1895,  ii,  p.  1213. 

Laws.     Journ.  of  Amer.  Med.  Assn.,  xxxi,  p.  793. 

Wiggers.     Arch.  Int.  Med.,  viii,  p.  17. 

Rost,  Fram  u.  Heise.     Arb.  d.  Kais.  Gesundheitsamt,  xxxii,  p.  223. 

Wallace  and  Ringer.     Journ.  Amer.  Med.  Assn.,  1909,  ii,  p.  1629. 

Miller.     Ibid.,  1910,  p.  1666. 

XX.     THE  DIGITALIS  SERIES. 

The  digitalis  series  embraces  a  considerable  number  of  substances 
which  are  characterized  by  their  action  on  the  heart.  They  are  widely 
distributed  in  the  vegetable  kingdom  in  very  different  botanical  fam- 
ilies, and  have  long  been  in  use  for  various  purposes  in  civilized  and 
uncivilized  countries.  Some  of  them  were  employed  as  remedies  by 
the  laity  long  before  their  virtues  were  recognized  by  the  medical 
profession,  while  others  have  been  used  as  arrow  poisons  by  the  natives 
of  different  parts  of  Africa  and  of  the  Eastern  Archipelago. 

The  most  important  plants  which  contain  bodies  belonging  to  this 


396  SUBSTANCES  ACTING  AFTER  ABSORPTION 

group  arc  DigitnUs  imrp^irea  (purple  foxglove),  Strnphanthiis  his- 
pidiis,  or  Koinhe,  aud  SriJla  maritima  (squills).  Others  which  are 
less  frequcMitly  used  are  Ilrllcboriis  nigcr  (Christinas  rose),  Conml- 
laria  majalis  (lily  of  the  valley),  Apocynum  cannabiniim  (Canadian 
hemp),  and  Adonic-  vernal  is  (pheasant's  eye).  Similar  effects  are 
obtained  from  bodies  contained  in  other  species  of  these  genera  and 
in  a  large  and  ever-growing  list  of  other  plants,  such  as  Antiaris 
(Upas  tree),  Ner'mm  (oleander),  Acocanthera  (ouabaio),  Erythro- 
phlosuin  (sassy  bark  or  Casca  bark),  Thevetia,  Urechites  and  Coro- 
nilla.  Numbers  of  other  plants  are  said  to  resemble  digitalis  in  their 
effects,  but  until  this  has  been  shown  by  more  careful  investigation, 
it  is  undesiral)le  to  add  them  to  the  above  list,  which  is  already  exten- 
sive enough.  These  bodies  are  not,  however,  confined  to  the  vegetable 
kingdom,  for  Faust  and  Abel  have  isolated  substances  from  toads, 
which  induce  the  same  changes  in  the  heart.  Salts  of  barium  also 
induce  many  of  the  changes  characteristic  of  this  series. 

The  active  principles  of  the  plants  of  this  group  present  many 
points  of  resemblance,  and  some  of  them  which  are  now  believed  to 
be  distinct,  may  prove  to  be  identical.  Their  isolation  is  attended 
with  considerable  difficulty,  as  many  are  amorphous,  and  but  few  of 
them  form  combinations  with  the  ordinary  chemical  reagents.  INIost 
of  them  are  glucosides,  others  are  indifferent  bodies,  and  one  or  two 
are  alkaloids.  There  are  often  found  in  a  plant  several  distinct 
bodies  belonging  to  this  series,  and  these  may  again  be  accompanied 
by  others  which  induce  the  same  symptoms  as  picrotoxin  or  saponin. 

Digitalis  has  been  more  carefully  examined  from  the  chemical  point 
of  view  than  the  other  plants,  but  even  its  active  principles  are  still 
only  partially  known,  and  the  subject  is  yet  in  an  unsatisfactory  state; 
for  the  amount  and  character  of  the  active  constituents  seem  to  vary 
not  only  in  different  seasons  and  in  plants  grown  in  different  soils,  but 
also  in  different  parts  of  the  same  plant.  The  pharmacopanal  pre- 
parations are  made  from  the  leaves,  in  which  two  glucosides,  Digitoxin 
and  Digitalein  (or  Gitalin),  have  been  found  possessing  the  character- 
istic cardiac  action,  along  with  some  other  glucosides  (Digitsaponin, 
Gitin),  which  do  not  affect  the  heart  but  appear  to  resemble  saponin 
and  like  it  suspend  insoluble  bodies  in  water;  another  glucoside,  Digito- 
phyllin,  has  been  found  by  some  chemists  but  is  not  so  definitely  estab- 
lished as  digitoxin  and  digitalein.  Digitoxin  is  soluble  in  alcohol,  but 
not  in  water  when  pure,  while  digitalein  is  S()lul)le  in  both  water  and 
alcohol.  The  infusion  thus  contains  digitalein  with  traces  of  digitoxin 
dissolved  in  the  presence  of  the  other  glucosides,  while  the  tincture 
contains  digitoxin  and  digitalein  with  less  of  the  saponin  bodies. 

The  seeds  of  digitalis  are  not  pharmacopoeial,  but  are  extensively 
used  for  the  ])reparation  of  the  so-called  digitalines  of  connnerce. 
They  contain  another  cardiac  glucoside,  Jhgitalui,  and  digitalein  in 
large  amounts  with  a  small  percentage  of  digitoxin  and  Digitonin, 
another  glucoside  resembling  saponin  in  character.  The  prejiarations 
from   the   seeds  thus  diiVer  entirely  from  the  Cialenical  j)rej)aratioiis, 


THE  DIGITALIS  SERIES 


397 


which  are  formed  exchisively  from  the  leaves,  and  most  chnicians  find 
them  less  satisfactory  in  practice.  Digitoxin  is  much  the  most  powerful 
constituent,  and  the  small  amount  in  which  it  is  present  in  the  digitalines 
prepared  from  the  seeds  probably  accounts  for  their  unsatisfactory 
effects  in  therapeutics. 

The  various  species  of  Strophanthus  contain  glucosides  which  present 
differences  in  chemical  form  and  also  in  toxicity  but  resemble  each 
other  in  their  common  action  on  the  heart.  The  species  in  common 
use  are  Strophanthus  Kombe  and  Strophanthus  hispidus,  whose  gluco- 
sides  resemble  each  other  closely  in  action  and  are  known  as  Kombe- 
sfrophanthin  and  Hispidus-strophanthin.  Strophanthus  gratus  (or 
glaber)  contains  a  crystalline  glucoside  known  as  Gratus-strophanthin 
{g-strophanthin  of  Thoms)^  The  strophanthin  of  commerce  is  gener- 
ally derived  from  a  mixture  of  different  species  and  varies  much  in 
composition  and  toxicity. 

Scilla  maritima,  or  squills,  contains  one  or  more  glucosides,  which 
have  not  been  isolated.    Saponin  bodies  are  also  present. 


Convallamarin  (obtained  from  Convallaria) ,  Adonidin  (Adonis),  Okandrin, 
Xeriin  and  Neriodorin  (Nerium),  Euonymin  (Euonjanus),  Antiarin  (Antiaris), 
Thevetin  and  Cerberin  (Thevetia),  Cheiranthin  (Cheiranthiis),  CoroniUin  (Cor- 
onilla),  Tanghinin  (Tanghinia  venenifera)  are  glucosides,  while  Cynotoxin  or 
apocynamarin  (Apocynum)  is  indifferent  and  Erythrophlodne  (Erj'throphla'um 
guinense)  is  a  glucosidal  alls:aloid. 

With  the  exception  of  the  last,  then,  the  members  of  this  series  which  have 
been  examined  hitherto  are  either  glucosides  or  indifferent  substances,  con- 
taining carbon,'  hydrogen,  and  oxj'gen,  but  no  nitrogen.  They  are  all  liable 
to  decompose  when  kept  long  in  watery  solutions,  and  especially  when  heated 
with  acids,  and  then  frequently  form  substances  which  no  longer  possess  the 
digitalis  action,  but  are  rather  to  be  classed  with  picrotoxin.  Erythrophloeine 
and  a  more  recently  isolated  alkaloid,  Mumvine,  which  resembles  it  in  most 
respects,  split  off  a  molecule  of  sugar  when  they  are  boiled  with  acids.  In 
many  of  these  plants  several  glucosides  appear  to  be  present  and  few  of  them 
have  as  yet  been  estabhshed  as  pure  substances.  The  cardiac  glucosides  are 
very  generally  accompanied  by  others,  which  belong  to  the  saponin  series,  and 
have  not  the  typical  digitahs  action.  Helleborein,  which  occurs  in  Helleborus 
niger  along  with  Helleborin,  appears  to  form  a  connecting  link  between  these 
two  groups,  possessing  some  of  the  properties  of  digitalis,  but  tending  to  dis- 
solve the  blood  cells  like  saponin. 

Symptoms. — Digitalis  taken  in  even  large  medicinal  doses  in  health 
provokes  no  symptoms  unless  the  dose  is  frequently  repeated.  Poison- 
ous quantities  induce  nausea  and  vomiting  with  abdominal  pain,  and 
often  diarrhoea.  The  patient  complains  of  general  depression,  headache, 
giddiness  and  precordial  discomfort  and  often  pases  into  a  stage  of 
great  muscular  w^eakness  and  collapse.  The  pulse  first  becomes  inter- 
mittent and  then  beats  regularly  at  about  40  per  minute.  Later,  it 
•  may  become  rapid  and  irregular,  and  fatal  coma  follows.     The  symp- 

^  This  g-strophanthin  seems  to  be  identical  with  the  ouabain  formerly  obtained  from 
some  species  of  Acoeanthera,  in  which  it  is  accompanied  by  acocantherin,  another  cardiac 
glucoside. 


398  SUBSTANCES  ACTING  AFTER  ABSORPTJON 

toins  soniethnes  appear  only  several  hours  after  the  poison  has  been 
taken  and  last  for  several  days  in  cases  which  survive. 

A  much  more  common  form  of  poisonin<,'  arises  from  the  prolonged 
use  of  therapeutic  doses.  Here  the  chief  symptoms  are  headache,  giddi- 
ness, nausea  and  vomiting  and  in  some  cases  marked  slowing  of  the 
pulse.  These  symptoms  disappear  within  forty-eight  hours  if  the  treat- 
ment is  stopped  or  the  dose  reduced. 

Action. — The  digitalis  series  possesses  a  local  and  a  general  action. 
The  Local  Effects  consist  in  primary  irritation,  followed  frequently 
l)y  paralxsis  of  the  sensory  nerve  endings.  Thus  in  the  eye  a  small 
quantity  of  a  solution,  or  a  minute  particle  of  the  dry  poison  causes 
the  most  intense  pain,  redness  and  congestion  of  the  conjunctiva,  and 
all  the  symptoms  of  acute  inflammation.  On  the  tongue  the  bitter 
taste  is  followed  by  burning  pain  frequently,  and  if  the  powder  be 
drawn  into  the  nostrils  and  larynx,  marked  swelling  of  the  mucous 
membrane,  sneezing,  coughing  and  hoarseness  are  produced  in  many 
persons.  They  have  little  action  on  the  skin,  although  here  too  smart- 
ing is  occasionally  produced;  but  when  injected  subcutaneously  many 
of  them  cause  marked  inflammation,  which  not  infrequently  ends  in 
the  formation  of  abscesses,  even  although  the  injection  has  been  abso- 
lutely aseptic.  A  similar  irritant  action  in  the  stomach  may  contribute 
toward  the  characteristic  emetic  action  of  this  series,  but  the  main 
factor  here  is  action  in  the  medulla  oblongata.  This  irritant  action 
is  not  equally  marked  throughout  the  series,  however,  for  digitoxin  is 
much  the  most  powerfid  in  tliis  respect,  while  digitalin  may  be  injected 
subcutaneously  without  danger  and  without  pain.  The  local  annesthetic 
property  is  likewise  not  equally  developed  in  all  the  members  of  the 
series;  several  of  them  (strophanthin,  erythrophloeine)  have  been  sug- 
gested as  local  antiesthetics  for  the  eye,  but  their  ])rimary  irritant  effect 
precludes  their  use  for  this  purpose. 

After  absorption,  the  chief  symptoms  are  due  to  their  action  on  the 
central  nervous  system  and  the  heart.  The  action  on  the  Central 
Nervous  System  is  frequently  ignored  or  attributed  to  the  changes  in  the 
heart  as  a  secondary  efl'ect,  but  there  is  undoubtedly  a  stimulation  of 
some  of  the  nerve  centres,  quite  independent  of  the  action  on  the 
heart.  This  stimulati(Mi,  like  that  of  picrotoxin,  seems  almost  entirely 
limited  to  the  medulla  oblongata  in  many  cases.  In  the  frog  the  excita- 
biHty  of  the  reflexes  is  often  lowered  by  members  of  this  series,  ])r()bably 
because  of  the  intense  stinnilation  of  the  medulla  oblongata;  but 
sometimes  a  distinctly  increased  irritability  is  observed.  These  altera- 
tions are  inucli  greatiT  that  those  caused  by  the  internii)tion  of  the 
circulation,  and  are  therefore  independent  of  the  action  on  the  heart, 
to  which  they  have  been  erroneously  ascribed.  ]\Iore  marked  symptoms 
are  |)ro(hice(l  in  inamnials,  however,  by  this  central  nervous  stimulation, 
for  in  these  vomiting  is  elicited  very  soon  after  the  injection  of  large 
(|iiaiititi<'s.  long  before  the  heart  is  very  seriously  alTected.  and  this  is 
nndoubtedly  due  to  action  on  the  medulla  oblongata.  To  the  same 
cause  is  to  be  attributed  the  rai)id,  deej)  respiratory  movements  and 


THE  DIGITALIS  SERIES 


399 


convulsions,  which  are  often  observed  in  the  later  stages  of  poisoning 
and  which  are  evidently  not  due  to  cerebral  ansemia,  as  has  been  sup- 
posed, for  the  brain  at  this  stage  receives  quite  as  much  or  more  blood 
than  it  normally  does.  Even  small  quantities,  such  as  are  used  thera- 
peutically, cause  stimulation  of  certain  parts  of  the  central  nervous 
system,  for  the  stimulation  of  the  inhibitory  cardiac  centre  in  the 
medulla  often  slows  the  heart  both  in  therapeutics  and  in  experiments 
on  mammals. 

The  central  nervous  system,  then,  undergoes  distinct  stimulation 
under  digitalis.  This  stimulation  by  small  quantities  seems  limited 
to  the  inhibitory  cardiac  centre  in  the  medulla  oblongata,  but  \^hen 
larger  doses  of  digitalis  and  its  allies  are  injected,  other  parts  of  the 
medulla  become  stimulated,  and  vomiting,  increased  respiration,  and 
eventually  general  convulsions  may  be  produced. 

The  extent  to  which  the  members  of  this  series  act  as  stimulants  to 
the  nervous  centres  varies,  but  as  yet  little  comparative  work  has  been 
done  in  this  direction. 

The  action  of  the  Heart  is  the  most  important  of  all,  and  is  what 
distinguishes  digitalis  and  its  allies  from  all  other  substances.  This 
action  has  been  studied  most  carefully  in  the  frog,  and  is  here  found  to 
be  due  to  alterations  in  the  cardiac  muscular  tissue.  These  are  of  two 
distinct  kinds  which  frequently  oppose  each  other  and  thus  give  rise 
to  varying  results  in  different  hearts  and  under  different  doses.  The 
power  of  conducting  impulses  is  distinctly  reduced,  and  this  makes 
itself  e\'ident  in  the  frequent  failure  of  an  impulse  to  pass  from  the 
auricle  to  the  ventricle,  which  thus  remains  at  rest  during  a  full  cycle; 
very  often  each  alternate  impulse  of  the  auricle  thus  fails  to  reach  the 
ventricle,  giving  rise  to  half  rhythm;  or  the  ventricle  may  remain  in 
diastole  during  a  series  of  auricular  contractions,  or  may  cease  altogether 
in  this  position,  if  very  small  quantities  have  been  injected.  This 
depressant  action  on  conduction  is  accompanied  by  a  less  marked 
reduction  of  the  rate  of  the  auricle  and  sinus,  which  appears  to  arise 
from  diminished  spontaneous  excitability  of  the  tissue  from  which  the 
rh\i:hm  originates. 

Along  with  this  depression  of  conduction,  there  is  a  progressive  change 
in  the  contractility  of  the  heart.  The  beats  of  both  auricle  and  ventricle 
are  at  first  stronger  and  the  output  is  larger,  especially  if  the  heart  has 
been  weakened  by  long  exposure  or  other  measures.  Soon,  however, 
the  relaxation  becomes  imperfect,  and  the  output  falls  accordingly; 
though  the  ventricle  continues  to  empty  itself  more  completely,  it 
no  longer  contains  as  much  blood  at  the  l)eginning  of  systole  as  before. 
Soon  the  apex  of  the  ventricle  remains  contracted  during  the  diastole 
and  remains  motionless  and  white,  and  this  state  of  contraction  slowly 
spreads  over  the  rest  of  the  chamber,  until  the  ventricle  receives  no 
more  blood  from  the  auricular  systole,  and  the  auricles,  unable  to  empty 
themselves,  come  to  a  standstill  in  the  dilated  position. 

As  a  general  rule  both  these  actions  may  be  observed  intermingled  in 
the  frog's  heart  under  digitalis;  the  effects  of  the  depressed  conduc- 


400 


SUBSTANCES  ACTING  AFTER  ABSORPTION 


tivity  generally  precede  those  of  the  changed  contractility  and  are 
elicited  especially  by  very  small  doses.  Thus  when  the  minimal  lethal 
dose  is  given,  the  ventricle  is  very  often  found  in  diastolic  standstill 
from  its  failure  to  receive  impulses  from  the  auricle;  but  if  it  is  now 
stimulated  mechanically  or  electrically,  it  passes  into  complete  and 
permanent  systole.  When  larger  quantities  are  given  the  effects  on 
contractility  are  elicited  in  larger  measure,  and  there  may  be  little 
tendency  to  ventricular  intermission  until  the  chamber  is  in  almost 
complete  systolic  arrest. 

The  excitability  of  the  frog's  heart  muscle  is  augmented  by  digitalis; 
thus  if  salt  solution  is  led  through  the  excised  heart  for  some  time,  it 
ceases  to  beat,  but  if  digitalis  is  now  added  to  the  perfusing  solution 
rh\'thmical  contractions  often  return.  This  increased  excitability  may 
account  for  a  temporary  acceleration  of  the  heart  rate  which  is  some- 
times seen  in  the  frog  under  digitalis. 

Fig.  45 


¥' 

w^ 

^^WP 

IliPIIIII 

Hi''     ' 
"  ''    ■  '      ■  . 

'ivi'SiffljjHJII 

is 

jO                  f;                   Vl''l*'i|" 

sg 

J^^j^^/H^^jt/j/M^^^^^^^^^^^^M 

■ 

■ 

MMWl 

Tracing  of  the  movements  of  the  frog's  ventricle  under  one  of  the  digitalis  scries.  A, 
normal;  B,  digitalis  applied;  C,  half  rhythm  begins,  and  the  diastole  rapidly  becomes  less 
complete  until  the  ventricle  ceases  in  a  position  of  semicontraction.  A',  diagram  of  the 
heart  in  normal  condition;  a,  auricle;  v,  ventricle;  the  dotted  line  represents  the  outline 
in  full  systole;  the  continuous,  the  outline  in  diastole.  D',  outline  of  the  heart  in  stand- 
still after  digitalis;  the  ventricle,  v,  is  fully  contracted,  while  the  auricles  are  dilated. 
(After  Sluytermann.) 

The  action  on  the  frog's  heart  is  a  direct  one  on  the  nuiscle;  the 
inhibitory  mechanism  has  nothing  to  do  with  the  change  in  the  con- 
duction or  with  that  in  the  contractility,  for  the  application  of  atropine 
has  no  effect  upon  either  feature.  The  muscle  of  the  frog's  heart  is 
thus  reduced  in  conductivity  and  augmented  in  contractility  and  excita- 
bilit>-  by  members  of  this  series;  the  effect  on  the  conductivity  is  elicited 
by  smaller  quantities  than  are  necessary  to  change  the  contractility. 
Schmiedeberg  suggested  that  the  systolic  arrest  is  due  to  a  great  increase 
in  the  elasticity  of  the  heart  muscle,  but  this  is  not  supported  by 
later  investigations  and  is  insufficient  to  explain  the  phenomena. 

The  hearts  of  some  invertebrates  are  said  to  undergo  changes  similar 
to  those  described  in  the  frog's  heart,  while  the  crustacean's  seems  to 
be  entirrly  nnallVcted  by  digitalis. 

Mammalian  Heart.  In  the  mammalian  heart  digitalis  and  its  allies 
:ils()  all'cct  the  nnisch-  directly,  bnt  tins  is  complicated  by  inhibitory 
action,  which  is  absent  in  the  frog.    The  nuiscular  action  is  seen  in  the 


THE  DIGITALIS  SERIES 


401 


mammal  almost  only  in  the  increase  in  the  contractility  and  excital)ility, 
while  there  is  little  evidence  of  the  depressed  conduction  which  has 
been  described  in  the  frog's  heart.  Symptoms  of  reduced  conduction 
occur  in  the  mammal  it  is  true,  but  here  they  arise  for  the  most  part 
from  inhibitory  stimulation  and  not  from  direct  muscular  effects. 

The  action  of  digitalis  and  its  allies  on  the  mammalian  heart  may  be 
(li\-ided  into  three  stages,  of  which  the  first  and  third  are  always  de- 
veloped when  sufRcient  quantities  are  administered.  The  second  stage 
may  be  absent  in  certain  circumstances,  but  is  also  generally  present 
in  poisoning. 

Fig.  46 


D 


N' 


D 


N 


Tracings  of  the  ventricular  contractions  under  digitalis  in  experiments  on  two  dogs. 
iV,  A^',  normal  contractions.  D,  D',  contractions  under  digitalis.  The  levers  move  up- 
ward during  systole.  In  D  the  rhythm  is  slower  and  the  movements  extend  further 
upward  and  downward  than  in  iV,  i.  e.,  the  contractions  are  more  complete  and  the  dila- 
tation during  diastole  is  greater.  In  D'  the  rhythm  is  slower,  and  the  tracing  extends 
further  upward  than  in  N',  but  reaches  almost  the  same  point  below,  i.  e.,  the  contraction 
is  stronger,  but  the  dilatation  is  scarcely  changed.  Contrast  the  effects  of  inhibition  alone 
in  Figs.  30  and  32  (pp.  324  and  341). 

In  the  first  or  therapeutic  stage  of  the  action  of  this  series,  the 
rhythm  of  the  heart  is  changed,  and  the  extent  of  contraction  and 
relaxation  of  the  ventricle  and  auricle  undergo  certain  modifications 
(Fig.  46).  The  rhythm,  of  the  heart  is  distinctly  slower  than  before 
giving  the  drug,  for  the  inhibitory  apparatus  is  set  in  activity,  and 
the  slowing  is  accordingly  due  to  a  prolongation  of  the  pause  in  dias- 
tole. The  ventricles  contract  to  a  smaller  size,  that  is,  they  empty 
themselves  much  more  completely  than  they  normally  do.  It  is  now 
universally  recognized  that  the  normal  ventricle  does  not  empty  itself 
completely;  that  even  at  the  end  of  its  systole  there  still  remains  some 
blood  in  its  interior.  After  the  action  of  this  group  has  begun,  how- 
ever, the  blood  remaining  at  the  end  of  systole  is  much  less  than 
before.  This  increased  contraction  is,  like  that  in  the  frog's  heart, 
due  to  action  on  the  cardiac  muscle.  The  papillary  muscles  undergo 
the  same  changes  as  the  rest  of  the  ventricular  wall,  contracting  more 
strongly  and  more  completely  than  before  the  administration  of  the 
drug. 

The  relaxation  of  the  ventricle  is  found  to  vary  in  different  condi- 
tions. If  the  heart  is  weak  and  dilated,  digitalis  and  its  allies  tend 
to  lessen  this  dilatation,  that  is,  the  relaxation  of  the  ventricle  during 
26 


■402 


SUBSTANCES  ACTING  AFTER  ABSORPTION 


Fig.  47 


B 


diastole  is  less  than  before  the  administration  of  the  drug.  (See  Fig. 
47.)  If,  however,  the  heart  is  normal,  or  does  not  dilate  much  during 
diastole,  digitalis  increases  the  relaxation  (Fig.  4G,  D).  The  varia- 
tion in  the  degree  of  dilatation  of  the  ventricle  depends  upon  the 
opposing  factors — the  inhibition  and  the  muscular  action.  If  the 
inhibition  be  the  stronger,  the  ventricle  relaxes  more  completely  than 
before,  for  vagus  stimulation  always  tends  to  increase  the  relaxation 
of  the  heart.    If,  on  the  other  hand,  the  muscular  action  predominates 

the  relaxation  is  lessened, 
for  here,  as  in  the  frog's 
heart,  this  series  tends  to 
lessen  the  extent  of  relax- 
ation. In  the  normal  heart 
the  application  of  one  of 
tnis  series  causes,  as  a 
general  rule,  an  increase  in 
the  extent  of  relaxation. 
It  must  be  added  that 
the  inhibition  is  due  to 
the  stimulation  of  the 
\'agus  centre  in  the 
medulla  only;  the  per- 
ipheral mechanism  is  not 
involved,  for  digitalis 
does  not  slow  the  heart 
after  section  of  the  vagi, 
as  it  would  do,  if  it 
acted  on  the  intracar- 
diac inhibitory  ganglia  or 
nerve  ends. 

If,  then,  the  ventricles 
contain  more  blood,  at  the 
beginning  of  systole,  i.  e., 
are  more  relaxed  than 
usual,  and  if  the  quantity 
remaining  at  the  cud  of 
systole  is  less  than  nor- 


Tracings  of  the  movements  of  the  ventricle  (lower) 
and  auricle  (upper)  under  digitalis.  During  systole 
the  levers  make  an  upstroke.  In  this  experiment  the 
inhibitory  terminations  had  been  paralyzed,  so  that 
only  the  muscular  action  is  developed.  A,  normal;  B, 
after  digitalis.  The  rhythm  of  the  heart  is  slightly 
accelerated  in  B,  and  the  levers  extend  further  up- 
wards, indicating  a  more  perfect  systole  in  both  auricle 
and  ventricle.  The  ventricular  lever  does  not  reach  so 
far  downward  in  B,  i.  e.,  the  ventricular  diastole  is  less 
complete. 


mal,  the  heart  must  expel 
much  more  blood  at  each  ventricular  contraction  than  it  does  normally 
(see  Fig.  48).  Even  though  the  amount  of  blood  at  the  beginning 
of  systole  is  unchanged  or  slightly  diminished  (lessened  dilatation), 
as  occasionally  happens,  the  amount  expelled  is  increased  because  the 
ventricles  contract  more  completely.  If  the  number  of  beats  per 
minute  remained  the  same,  therefore,  the  amount  of  blood  expelled 
(or  the  out])ut)  would  bo  much  increased;  but  the  rhythm  is  slower 
than  normal,  and  although  each  beat  i)roj)cls  a  larger  amount  of  blood 
into  the  aorta  and  ])ulnioiiary  artery  tlian  normally,  it  is  not  impos- 
sible that  the  output  ni;i,\-  be  less  than  before  the  drug  was  admin- 
istered.    In  the  therapeutic  use  of  these  drugs  the  slowing  is  not  great 


THE  DIGITALIS  SERIES 


403 


k. 

^^ 

l^H 

B 

p 


^ 


A 


B 


C 


enoiigli  to  (•()iiiiter})alaiice  the  increased  oiiti)iit  per  beat,  and  a  larger 
amount  of  blood  is  therefore  dri\'en  into  the  aorta  and  pnhnoiiary 
artery. 

The  C'lianges  in  the  ventricle,  then,  are  due  to  inhibitory  activity 
and  to  direct  cardiac  action,  the  first  tending  to  lessen  the  number  of 
beats,  to  increase  the  relaxation  of  the  fibres  and  to  weaken  the  systole, 
and  thus  to  diminish  the  output  and  efficiency  of  the  heart;  the  second 
tending  to  strengthen  the  systole  and  thus  to  augment  the  output, 
while  also  limiting  the  dila- 
tation, which  may  increase  Fig.  48 
or  lessen  the  efficiency  of  the 
heart  according  to  circum- 
stances. 

In  the  auricles  the  same 
two  agencies  are  found  in 
opposition,  the  inhibitory 
stimulation  and  the  muscular 
action.  Stimulation  of  the 
inhibitory  nerves  causes  in 
the  auricle  more  or  less  in- 
crease in  the  dilatation,  while 
it  lessens  the  contraction 
considerably,  and  in  fact 
may  pre\^ent  it  entirely. 
The  muscular  action  of  this 
series  is  the  same  here  as 
in  the  ventricle,  causing  a 
tendency  toward  more  com- 
plete systole  and  less  com- 
plete relaxation.  After  small 
quantities,  such  as  are  used 
in  medicine,  the  rhythm  of 
the  auricle  is  slow,  like  that 
of  the  ventricle,  owing  to 
the  inhibition;  the  relaxation 
is  little  changed,  but,  owing 
to  the  muscular  action,  the 
contraction  is  more  complete. 
In  but  slightly  larger  quantities,  however,  the  inhibitory  action  causes 
a  less  complete  contraction,  so  that  the  work  done  by  the  auricle  is 
actually  less  than  before  the  injection. 

The  rhythm  of  the  different  parts  of  the  heart  is  exactly  the  same 
during  this  stage,  and  the  changes  seen  in  the  right  auricle  and  ven- 
tricle correspond  to  those  in  the  left. 

Some  observers  state  that  small  quantities  of  digitalis  change  the 
electrocardiogram,  in  certain  features,  but  these  changes  are  not  constant 
and  have  received  no  adequate  explanation,  so  that  they  do  not  require 
discussion  at  present. 


Diagram  to  illustrate  the  effect  of  digitalis  on 
the  output  of  the  ventricle.  A,  B,  C,  three  cylin- 
ders with  pistons  moving  up  and  down  in  them 
and  driving  out  fluid.  In  B  and  C  (digitalis  ac- 
tion), the  piston  descends  lower  than  in  A  (normal) 
and  in  B  it  can  also  rise  higher.  The  output  of 
each  stroke  is  represented  by  the  shaded  part  of 
the  cylinder  and  is  greatest  in  B,  in  which  more 
fluid  is  present  at  the  beginning  of  the  stroke  (dia- 
stole) and  less  at  the  end  of  the  stroke  (systole) 
than  in  A.  It  is  also  greater  in  C,  in  which  the 
same  amount  of  fluid  is  present  at  the  beginning 
of  the  stroke  (diastole)  as  in  ^,  but  less  is  present 
at  the  end  (systole).  If  the  pistons  make  the  same 
number  of  strokes  per  minute  in  A,  B,  and  C,  the 
amount  of  fluid  pumped  will  be  greatest  in  B  and 
least  in  A,  which  represents  the  normal  ventricle. 


404  SUBSTANCES  ACTING  AFTER  ABSORPTION 

If  larger  quantities  be  injected,  either  tlie  inhil)itory  or  tlie  mus- 
cular action  may  become  markedly  increased,  and  the  appearance  of 
the  heart  varies  according  to  which  of  these  predominates.  It  must 
be  distinctly  understood  that  the  following  symptoms  betoken  a  grave 
condition  of  poisoning. 

In  the  second  stage  the  symptoms  are  due  to  excessive  inhibitory 
acti\'ity,  while  the  direct  cardiac  action  is  less  developed.  The 
rhythm  of  the  ventricle,  and  consequently  of  the  pulse,  is  very  slow 
and  irregular,  as  is  always  the  case  when  the  inhibitory  apparatus  is 
strongly  stimulated  (see  Fig.  30,  p.  324).  During  diastole  the  ven- 
tricle dilates  more  completely  than  usual,  while  its  systole  continues 
powerful,  since  the  inhibitory  stimulation  increases  the  relaxation  but 
has  less  power  to  diminish  the  contractions.  The  relaxation  is  so 
marked,  however,  that  very  often  more  blood  remains  at  the  end  of  the 
contraction  than  before  the  drug  was  administered.  As  a  general  rule, 
however,  each  beat  expels  more  blood  than  normally,  because  the  heart 
is  engorged  before  the  systole  begins;  but  the  rhythm  is  so  slow  that 
the  output  per  minute  and  the  efficiency  of  the  heart  as  a  pump  is  less 
than  usual.  This  is  the  feature  which  differentiates  the  first  from 
the  second  stage,  in  which  the  same  factors  are  present;  in  the  first 
stage  the  efficiency  of  the  heart,  i.  e.,  the  amount  of  blood  expelled  per 
minute,  is  greater,  in  the  second  stage  it  is  less  than  before  the  adminis- 
tration of  the  drug. 

Not  infrequently  the  auricle  and  ventricle  beat  in  different  rhythms, 
the  ventricle  developing  a  spontaneous  rhythm  which  may  be  either 
faster  or  slower  than  that  of  the  auricle.  This  is  apparently  due  to 
the  inhibitory  action,  which  blocks  the  passage  of  impulses  from  the 
auricle  to  the  ventricle,  although  the  effect  of  the  drug  in  increasing 
the  irritability  of  the  cardiac  muscle  contributes  to  it  by  facilitating 
the  development  of  the  spontaneous  ventricular  rhythm. 

The  auricular  contractions  are  much  weaker  than  in  the  first  stage, 
and  even  than  in  the  normal  heart,  and  may  cease  altogether  for  some 
time,  while  the  chambers  do  not  tend  to  dilate  further  as  a  general 
rule. 

This  stage  of  excessive  inhibition  is  not  observed  in  every  case  of 
poisoning  in  animals,  nor  prol)ably  in  man,  although  in  the  recorded 
instances  of  poisoning  with  the  members  of  this  series,  it  seems  to  have 
been  present,  as  the  pulse  is  said  to  have  been  very  slow  and  irregular. 
When  this  very  slow  (40-50  per  minute)  and  irregular  pulse  is  met 
in  the  therapeutic  use  of  digitalis  and  its  allies,  it  indicates  that  the 
efficiency  of  the  heart  is  lessened  by  the  drug  instead  of  being  increased, 
and  the  dose  should  be  reduced  immediately.  If  the  inhibitory  mechan- 
ism is  weak,  or  is  paralyzed  by  the  preliminary  injection  of  such  drugs 
as  atropine,  the  second  stage  is  entirely  absent. 

When  very  large  quantities  of  any  of  this  series  are  injected,  the 
tlilrd  sinxje  sets  in.  It  is  preceded  by  the  first  for  a  short  time,  gener- 
ally by  l)oth  first  and  second.  In  this  stage  the  ventricular  rhythm 
becomes  verv  nmch  accelerated,  often  bevond  the  normal,  and  even 


THE  DIGITALIS  SERIES 


405 


hoyoucl  that  seen  after  paralysis  of  the  hihibitory  nerves.  Tliis  accel- 
eration is  not  produced  by  paralysis  of  the  vagus,  for  stinuilation  of 
this  nerve  sometimes  still  slows  the  heart  and  always  causes  dilatation. 
It  is  really  due  to  the  drug  increasing  the  irritability  of  the  heart  muscle 
to  such  an  extent  that  the  inhibitory  apparatus  is  no  longer  able  to 
hold  it  in  check. 

Fig.  49 


Tracing  of  the  auricular  (upper)  and  ventricular  movements  (lower)  under  digitalis, 
as  the  first  stage  passes  into  the  second.  During  systole  the  levers  move  upward,  during 
diastole  downward.  The  rhythm  of  the  two  chambers  is  at  first  the  same,  but  soon  changes, 
the  auricle  maintaining  its  rapid  beat  while  the  ventricle  becomes  slow  and  irregular. 
At  the  end  of  the  tracing  the  ventricle  again  becomes  rapid,  while  the  auricle  becomes  slow. 
The  strength  of  the  contractions  and  the  extent  of  relaxation  of  the  ventricle  muscle 
remain  little  altered,  while  the  auricle  rapidly  weakens  in  strength,  but  improves  again 
at  the  end  of  the  tracing. 

The  auricles  also  undergo  the  same  changes.  They  begin  to  accel- 
erate their  rhythm,  which  may  continue  the  same  as  that  of  the  ven- 
tricle for  some  time,  but  generally  diverges  from  it  in  course  of  time. 
If,  however,  the  ventricular  rhythm  has  been  independent  of  the 
auricular  in  the  second  stage,  the  auricles  are  often  later  in  being 
accelerated  than  the  ventricles,  because  the  inhibitory  nerves  act  more 
strongly  on  them.  The  difference  in  rhythm  of  the  two  divisions 
leads  to  a  very  characteristic  periodic  variation  in  the  strength  of  the 
contractions  of  both  auricle  and  ventricle  (Fig.  50).  This  auriculo- 
ventricular  arrhythmia  may  continue  for  some  time,  but  further  irreg- 
ularities soon  present  themselves.  At  intervals  extrasystoles  of  either 
ventricle  or  auricle  appear,  that  is,  two  contractions  follow  so  rapidly 
on  each  other  that  the  chamber  has  no  time  to  dilate  fully  between 
them  and  no  blood  is  expelled  by  the  second  one.  These  extrasystoles 
become  more  numerous,  and  soon  form  groups  of  two  or  three,  sepa- 
rated by  other  groups  of  ordinary'  contractions.  The  rhythm  becomes 
more  and  more  rapid,  and  other  forms  of  irregularity  appear.  Eventually 
the  auricle  generally  passes  into  fibrillary  contractions  while  the  rhythm 
of  the  ventricle  continues  to  increase,  and  the  force  of  its  contractions 
and  the  output  of  each  beat  decrease.  The  ventricle  finally  passes 
into  fibrillary  contractions  also,  and  the  circulation  is  arrested,  after 
which  the  heart  dilates  to  an  extreme  degree. 

All  the  features  of  the  third  stage  are  due  to  the  poison's  increas- 
ing the  spontaneous  excital)ility  of  the  heart  muscle.     This  increased 


406 


SUBSTANCES  ACTING  AFTER  ABSORPTION 


excitability  in  the  pacemaker  leads  to  acceleration  of  the  beat  of  the 
whole  heart,  but  larger  amounts  arouse  the  normally  dormant  areas 
in  the  auricle  and  ventricle,  and  lead  to  impulses  being  discharged 
from  them  and  causing  contractions  in  one  part  of  the  heart  which  are 
not  shared  in  by  the  rest  of  the  organ.  Later,  the  excitability  of  the 
ventricle  may  be  so  great  that  it  adopts  its  own  regular  rhythm  (Fig.  50) 

independent  of  that  of  the 
I'Ki.  50  auricle.     A  further  rise  in 

the  excitability  leads  to 
spontaneous  activity  of 
still  lower  areas  in  the 
auricle  and  'ventricle  so 
that  several  rhythms  are 
developed  in  each  cham- 
ber and  extrasystoles  occur 
more  or  less  regularly  (Fig. 
51).  Finally  these  mul- 
tiple rhythms  culuminate 
in  fibrillary  contractions  in 
each  chamber.  Almost  all 
the  characteristic  features 
of  this  stage  may  be 
imitated  in  the  normal, 
unpoisoned  heart  by  stim- 
ulating the  different  cham- 
bers by  electric  shocks;  the 
impulses  which  in  the 
poisoned  heart  arise  from 
its  own  excessive  irrita- 
bility, are  here  given  by 
the  artificial  stimuli,  but 
the  effect  is  the  same.  The 
output  of  the  heart  contin- 
ues much  augmented  dur- 
ing the  first  part  of  thethird 
stage,  but ,  asthe  irregularity 
of  the  ventricles  increases, 
and  the  extrasystoles  be- 
come more  numerous,  it  be- 
comes less  and  eventually 
falls  to  zero  when  the  heart 
passes  into  delirium. 
'  Tlironghont  the  whole  conrse  of  the  intoxication  the  ventricles  beat  in 
unison,  and  the  two  auricles  also  maintain  the  same  rhythm  throughout, 
bnt  the  rhythm  of  the  ventricles  may,  as  has  been  stated,  be  entirely 
dilVcrcnt  from  that  of  the  anriclcs  in  either  the  second  or  third  stage. 

A   certain   analog\    nia.N    l)c    drawn    between    the   changes  observed 
in   the   manmialian   heart   and   thosi-  described   in   the   frog,   with    the 


Tiarint-'s  i^f  auricle  (upper)  and  \entriele  (lower) 
in  tliird  stage  of  digitalis  action.  Auricle  and  ven- 
tricle each  beating  regularly  but  at  different  rates. 
The  levers  move  do\vii\var<]  in  sj^stolc,  upward  in 
diastole. 


THE  DIGITALIS  SERIES 


40< 


proviso  that  the  diminished  conduction  in  the  latter  is  of  muscular 
origin,  while  in  the  mammals  it  is  inhibitory  in  character.  The  heart 
in  mammals  is  generally  found  in  the  position  of  diastole  in  cases  of 
fatal  digitalis  poisoning,  and  this  has  been  supposed  to  indicate  a 
fundamental  tlifference  in  the  action  of  digitalis  on  the  amphibian 
and  mammalian  heart.  The  dilatation  is  not,  however,  a  direct  result 
of  the  digitalis,  but  is 
probably   induced    by    the  Fig.  51 

poisons  formed  in  the  heart         -.  ,  .  .  .  i .  .  , 

by  its  own  activity.  When 
the  mammalian  heart  is 
excised,  and  blood  contain- 
ing digitalis  is  perfused 
through  the  coronary  ves- 
sels, complete  systolic  stand- 
still of  the  ventricle  resem- 
bling that  seen  in  the  frog 
-is  often  the  final  outcome. 
In  both  frog  and  mammal 
the  increase  in  activity  is 
attended  by  an  augmented 
metabolism  in  the  heart. 

Vessels. — Small  quantities 
of  digitalis  and  its  allies,  such 
as  are  used  in  medicine,  have 
no  direct  action  on  the  blood- 
vessels, but  larger  amounts 

induce  changes  in  the  muscular  coat  which  present  some  analogy  to 
the  changes  in  the  heart  muscle.  The  latter  is  much  more  sensitive 
to  the  glucosides  than  the  arterial  walls  however,  and  an  amount  of 
digitalis  which  is  capable  of  acting  on  the  vessels,  proves  fatal  to  the 
heart  in  the  course  of  a  few  minutes.  The  vascular  action  has  thus 
no  therapeutic  importance.  It  may  be  observed  by  perfusing  the 
surviving  vessels  with  digitalis  in  Ringer's  solution;  in  these  experi- 
ments it  is  found  that  very  dilute  solutions  have  a  tendency  to  dilate 
the  vessels,  more  especially  those  of  the  kidney  and  limbs  (Kasztan, 
Fahrenkamp),  while  in  greater  concentration  the  vessels  are  uniformly 
contracted.  It  is  possible  to  find  a  strength  of  solution  which  dilates 
the  renal  vessels  when  perfused  through  them  and  contracts  those  of 
the  mesentery;  and  it  may  be  added  that  this  solution  perfused  through 
the  coronary  vessels  of  the  heart  arrests  it  in  systole  in  a  short  time. 
But  more  attention  has  been  paid  to  the  marked  contraction  of  the 
vessels  which  is  seen  on  perfusing  more  concentrated  solutions  through 
them.  The  glucosides  vary  considerably  in  their  power  of  contracting 
the  vessels  when  thus  perfused;  digitoxin  is  distinctly  more  powerful 
than  strophanthin  in  contracting  them  and  has  a  more  limited  action 
in  dilating  them.  The  different  vessels  also  vary  in  their  reaction, 
those  of  the  intestinal  area  contracting  more  readih'  than  those  of  the 


Tracing  of  the  ventricular  movements  in  the  last 
stage  of  digitalis  poisoning.  The  lever  moves  up- 
wards in  sj'stole.  The  characteristic  feature  is  the 
extreme  irregularity,  no  two  contractions  resembling 
each  other  in  form  or  strength. 


408       SUBSTANCES  ACTING  AFTER  ABSORPTION 

kidney,  wliich  again  appear  less  suscepti})le  tlian  those  of  tlie  limbs 
and  l)rain;  the  coronary  arteries  of  the  heart  a])j)ear  to  resenihle  those 
of  the  limbs  in  contracting  when  digitoxin  is  p)erfuscd  through  them, 
while  strophanthin  has  little  eHect  on  their  calibre;  but  in  the  living 
animal  more  blood  is  found  to  pass  through  the  coronary  under  digitalis 
and  also  under  strophanthin. 

The  Blood-pressure. — The  changes  in  the  heart  and  vessels  are  reflected 
in  the  blood-pressure,  and  it  is  possible  that  an  additional  factor  may 
be  involved  in  the  action  of  some  of  the  glucosides  on  the  vasomotor 
centre. 

In  man  therapeutic  doses  of  digitalis  have  not  been  found  to  cause 
any  ap])reciable  change  in  the  arterial  tension;  but  this  statement  must 
be  qualified  by  the  addition,  that  in  those  cases  in  which  digitalis  is 
most  beneficial,  the  blood-pressure  cannot  be  satisfactorily  determined. 
In  animals,  however,  quantities  of  digitalis  wdiich  are  sufficient  to 
affect  the  heart  do  not  increase  the  blood-pressure  appreciably.  The 
increased  efficiency  of  the  heart  in  itself  in  the  first  stage  would  increase 
the  arterial  tension,  but  this  appears  to  be  compensated  by  a  slight 
diminution  in  the  tone  of  the  vasomotor  centre,  which  reduces  the 
resistance  in  the  peripheral  vessels  and  thus  permits  a  freer  passage 
to  the  blood.  In  other  w^ords,  an  augmented  efficiency  of  the  heart 
must  lead  to  a  rise  in  blood-pressure  if  the  vessels  remain  unchanged 
in  calibre,  but  may  lead  to  an  accelerated  flow  through  the  tissues  if 
the  vessels  relax  in  proportion  as  the  output  of  the  heart  increases. 
Such  an  acceleration  of  the  circulation  has  been  observed  repeatedly 
under  small  quantities  of  digitalis  in  animals.  The  reduction  in  the 
tone  of  the  vasomotor  centre  is  not  due  to  the  glucosides  directly,  but 
arises  from  the  increased  efficiency  of  the  heart,  which  supplies  a  larger 
amount  of  blood  to  the  brain  and  thus  reduces  the  activity  of  the 
centre. 

As  long  as  this  compensatory  action  persists  in  the  ^'asomotor  centre, 
the  blood-pressure  does  not  rise  from  the  cardiac  action;  in  man  this 
balance  between  the  heart  and  the  vasomotor  centre  is  more  perfect 
than  in  the  lower  manunals  owdng  to  the  development  of  the  upright 
position,  and  in  man  changes  in  the  blood-pressure  are  thus  more 
carefully  guarded  against  and  no  alteration  is  caused  by  digitalis  in- 
creasing the  cardiiac  output.  Further,  in  cases  of  heart  failure,  in 
which  digitalis  is  prescribed,  the  vasomotor  centre  is  in  a  state  of  un- 
usual activity  because  the  circulation  is  deficient  and  the  supply  to  the 
brain  can  be  maintained  only  by  constriction  of  the  peri[)hcral  vessels. 
As  digitalis  improves  the  heart  and  increases  the  supply  of  blood  to 
the  brain,  the  vasomotor  centre  relaxes  its  activity,  and  thus,  while 
maintaining  the  brain  supply,  permits  more  blood  to  circulate  in  the 
(jther  vessels.  The  bl()0(l-i)ressure  does  not  increase  owing  to  this  com- 
jH'nsatory  factor. 

Ill  (•xpcriinciits  in  aiiiinals,  a  rise  in  hlood-prossure  is  ffcncrally  observed  under 
llic  tncnihcrs  of  tliis  ^roup,  partly  Ix-caiise  in  the  lower  nianinials  the  balance 
if)  less  developed  than  in  man  and  in  aildition  i.s  rendered  less  active  by  the 


I'HE  DIGITALIS  SERIES 


409 


anresthcsia,  but  mainly  because  niucli  larger  quantities  are  injected  in  oi-dcr 
to  induce  a  rapid  effect,  such  as  can  be  observed  in  the  course  of  an  hour.  These 
larger  doses  introduce  a  new  factor,  however,  in  the  direct  action  on  the  vessel 
walls,  which  precludes  the  compensatory  a(;tivity  of  the  vasomotor  centre,  and 
thus  the  blood-pressure  rises,  partly  from  the  increased  efficiency  of  the  lieart 
and  partly  from  the  unusual  resistance  to  the  passage  of  the  blood  out  of  the 
arteries.  And  this  appears  to  be  the  final  result  when  digitoxin  is  injected.  But 
when  strophanthin,  digitalin,  or  convallamarin  is  used,  a  further  complication 
arises,  for  these  have  a  somewhat  less  marked  vascular  action,  and  though  the 
vessels  of  the  abdominal  organs  are  contracted  in  the  same  way  as  by  digi- 
toxin, those  of  the  extremities  dilate.  This  dilatation  is  partly  owing  to  the 
increased  pressure  in  the  interior  overcoming  the  contraction  of  the  walls, 
but  is  mainly  to  be  ascribed  to  an  imperfect  compensatory  action  of  the  vaso- 
motor centre.    The  general  result  is  that  the  total  amount  of  blood  circulating 

Fig.  52 


Spleen 


^(«i*.A/»,,,>''.,;'^..A>''V«»«*v.#''wi»^'VV'»''' 

Blood  pressure  V 


j#;W#MW#ii#«iiMllW^ 


Tracings  of  the  blood-pressure  and  the  volume  of  the  leg  and  of  the  spleen  of  the  dog 
.under  strophanthus.  The  volume  of  the  leg  increases  with  the  blood-pressure,  i.  e., 
the  vessels  of  the  leg  are  dilated;  that  of  the  spleen  diminishes,  i.  e.,  the  vessels  are  con- 
tracted; 10  mg.  of  strophanthus  were  injected  intravenously  at  a,  followed  by  5  mg. 
at  b.    (Gottlieb  and  Magnus.) 


per  unit  of  time  is  increased,  but  this  increase  is  not  uniform  in  the  different 
organs.  Thus  both  strophanthin  and  digitalis  accelerate  the  flow  through  the 
lungs  and  through  the  peripheral  muscles  (Edmunds),  while  their  effects  on 
the  abdominal  organs  may  be  to  slow  the  current,  to  accelerate  it,  or  to 
leave  it  unaltered,  according  to  the  relative  degree  of  action  on  the  heart  and 
on  the  vessels. 

It  follows  that  in  animal  experiments  the  blood  tends  to  accumulate  on  the 
arterial  side  at  the  expense  of  the  venous,  for  more  blood  is  pumped  into  the 
arteries  and  it  has  greater  difficulty  in  escaping.  But  while  under  digitoxin 
the  different  regions  of  tlie  body  appear  to  be  equally  affected,  strophanthin, 
digitalin,  and  convallamarin  not  only  tend  to  accumulate  the  blood  on  the 
arterial  side,  but  divert  it  from  the  internal  organs  to  the  limbs.  In  man,  there 
being  no  increase  in  the  peripheral  resistance,  the  increased  efficiency  of  the 
heart  must  lead  to  an  acceleration  of  the  circulation. 

When  the  extreme  slowing  of  the  second  stage  appears  in  animal  experiments, 


410  SUBSTANCES  ACTING  AFTER  ABSORPTION 

the  output  of  the  heart  is  reduced,  and  the  pressure  in  the  aorta  and  the  velocity 
of  the  l)lood  may  become  subnormal  (Fig.  51^).  Wlicn  the  acceleration  of  the 
third  stage  follows,  the  output  is  again  augmented  and  the  constriction  of  the 
vessels  is  more  developed;  the  blood-pressure  rises  again  but  the  heart  soon 
becomes  irregular  in  the  foi-cc  of  its  contractions,  the  output  varies  from  second 
to  second,  and  the  pressure  in  the  aorta  falls  slowl}\  The  blood-pressure  tracing 
shows  the  irregularity  of  the  heart  more  or  less  accurately,  but  must  not  be 
taken  to  indicate  at  all  the  real  condition  of  that  organ,  as  the  constriction  of 
the  arterioles  varies  at  different  times.  Eventually  the  pressure  falls  to  zero, 
when  the  heart  ceases. 

In  experiments  on  animals  with  large  doses,  the  pressure  in  the  pulmonary 
artery  is  not  increased  by  strophanthin,  but  rises  under  digitalis  from  constric- 
tion of  the  vessels  similar  to  that  seen  in  the  systemic  circulation.  Tlie  action 
on  the  right  heart  is  similar  to  that  on  the  left  in  all  particulars. 

Fig.  5.3 

/\/l/VVWWWWVWl 


AHwa^/vV^Hvwwww 


III!  ii  nil  h  II  II  I      I  h  III!  II  Mil  ml     ml  II II II II II  II II     1 1  n  n  i  niinii      '  i  ii  iii  i  ii  1 1  ii  u- 
ABODE 

Blood-pressure  tracing  under  digitalis.  A,  normal;  B,  therapeutic  stage;  C,  exces- 
sive inhibition  causing  a  low  blood-pressure  from  lessened  output  of  the  heart.  D,  ex- 
cessive iiihiliition  with  some  irregularity  in  rhythm.  E,  third  stage  of  irregularity,  during 
which  the  blood-itressure  rises  again  from  the  increased  output  of  the  heart  and  the  further 
contraction  of  the  vessels. 

Action  on  the  Renal  Secretion.— "When  dijjitalis  was  first  introduced 
to  the  notice  of  tlie  medical  i)r()fession  by  Withering,  its  action  on  the 
heart  was  not  api)reciate(h  Withering;  used  it  only  to  remove  accu- 
mulations of  fluid  from  the  body,  whicii  it  accomplished  by  increasing 
the  secretion  of  urine.  This  observation  of  Withering  was  soon  con- 
firmed by  further  experience  in  the  use  of  this  drug,  but  it  was  long 
disputed  whether  this  diuretic  action  occurred  in  heakh,  or  whether  it 
was  not  confined  to  cases  in  which  pathological  accumuhitions  of  fhiid 
were  present.  Digitalis,  however,  as  is  now  conceded  by  almost  every- 
one, causes  some  increase  in  the  quantity  of  urine  secreted  by  tlie 
normal  animal,  although  this  is  small  ci)m])ared  witli  that  in  cases  of 
dropsy.  The  fhiid  of  tlie  urine  is  nuich  more  largely  augmented  than 
the  solids,  which  may  remain  unchanged.  This  increase  in  the  renal 
secretion  apjjcars  to  arise  not  from  a  direct  a<-tion  on  the  secretory 
mechanism,  such  as  it  met  with  under  caffeine,  but    onlx    indirectly, 


THE  DIGITALIS  SERIES 


411 


tlirougli  the  changes  in  the  circuhition;  the  kidney  shares  in  the  general 
acceleration  of  the  blood-current  and  functions  more  vigorously.  In 
experiments  on  animals  it  is  stated  that  small  quantities  of  digitalis 
constrict  the  vessels  of  the  kidney  less  than  those  of  the  intestine  and 
thus  divert  more  blood  to  the  kidney,  while  larger  doses  contract  the 
renal  vessels  along  with  those  of  the  other  abdofninal  organs  (Gottlieb 
and  Magnus).  And  in  accordance  with  this  it  has  been  observed  that 
a  larger  diuresis  sometimes  follows  from  moderate  doses  than  from 
very  large  ones,  and  that  the  diuresis  does  not  occur  at  the  maximum 
blood-pressure,  but  before  or  after  this  point;  the  diuresis  arises  then 
from  the  augmented  eflficiency  of  the  heart  and  not  from  any  vascular 


Fig.  54 


A    B    D 


D' 


D 


Diagram  representing  the  secretion  of  urine  in  a  rabbit  under  digitalis.  Each  rec- 
tangle represents  the  amount  of  urine  secreted  in  ten  minutes.  A  and  B,  normal  secretion. 
In  the  next  ten  minutes  a  small  dose  of  digitalis,  L>,  was  injected  intravenously  and  a  rapid 
increase  in  the  secretion  followed.  At  D'  and  D" ,  further  injections  were  made,  each 
being  succeeded  by  a  considerably  augmented  flow  of  urine.  The  dotted  line  represents 
the  averrfge  blood-pressure  at  each  period.  It  will  be  observed  that  each  injection  is 
followed  by  some  increase  in  the  arterial  tension.  Contrast  Fig.  21  (p.  285)  as  to  the 
amount  of  the  secretion,  and  also  as  to  the  behavior  of  the  blood-pressure. 


action.  This  augmented  efficiency  improves  the  nutrition  and  promotes 
the  activity  of  the  kidney  and  at  the  same  time  leads  to  a  more  n\\)'u\ 
circulation  in  the  lymphatic  system,  and  any  accumulation  of  fluid  in 
the  body  tends  to  be  absorbed  into  the  bloodvessels  and  to  be  excreted 
by  the  kidney.  It  is  possible,  also,  that  at  any  rate  some  of  the 
members  of  this  series  act  as  slight  irritants  to  the  renal  epithelium. 
The  appearance  of  blood  and  albumin  in  the  urine  of  animals  after 
large  doses  of  squills  and  digitalis  certainly  indicates  some  local  action 
apart  from  the  circuhitory  changes. 

The  Changes  in  the  Circulation  in  Man  can  be  foHowed  only  imper- 
fectly because  there  is  as  yet  no  means  of  measuring  the  strength  and 


412  SUBSTANCES  ACTING  AFTER  ABSORPTION 

effitieiuy  of  the  heart  eoiitractious.  In  many  eases  no  definite  alteration 
in  the  rhythm  follows  digitalis  treatment  even  when  it  is  pushed  until 
nausea  and  vomiting  occur.  In  others,  the  ])ulse  is  distinctly  slower, 
stronger  and  fuller  than  before  the  administration  of  the  drug.  It 
must  he  added  that  the  strength  of  the  pulse  is  not  to  be  regarded  as  a 
gauge  of  the  changes  in  the  cardiac  muscle,  for  it  is  due  not  only  to  the 
increased  strength  of  the  cardiac  contraction,  but  also  to  the  slow  rhythm. 
When  the  heart  is  beating  rapidly,  the  arteries  have  no  time  to  empty 
themselves  completely  and  the  pulse  is  small,  while  on  the  other  hand, 
when  digitalis  slows  the  heart,  the  arteries  have  time  to  empty  their 
contents  into  the  capillaries  before  the  next  contraction  occurs,  the 
walls  therefore  become  more  flaccid,  and  a  new  wave  of  blood  causes 
a  more  distinct  impulse.  Irreg^ularities  are  frequently  met  in  these 
cases  under  digitalis,  but  these  will  be  discussed  under  the  therapeutic 
uses;  in  other  instances  a  previously  irregular  pulse  becomes  less 
irregular.  In  cases  in  which  the  pulse  remains  unchanged  in  rate,  there 
may  be  other  evidences  of  the  action  of  the  drug,  such  as  an  increase  in 
the  secretion  of  urine  or  relief  of  dropsy  or  of  dyspnoea.  In  fever  and 
after  haemorrhage  the  pulse  is  especially  liable  not  to  show  any  slowing 
after  digitalis. 

The  blood-pressure  is  not  augmented  in  man  to  any  extent  per- 
ceptible by  the  methods  in  use  for  measuring  it  clinically,  and  in  some 
instances  it  is  distinctly  reduced,  as  has  been  stated  already  (p.  408). 

In  fever  the  Temperature  is  not  infrequently  reduced,  although  it 
remains  unchanged  after  the  administration  of  digitalis  to  the  normal 
animal.  This  action  is  said  by  some  to  be  the  result  of  collapse,  while 
others  believe  it  to  be  due  to  the  changes  in  the  circulation,  but  neither 
of  these  seems  to  be  a  very  happy  explanation.  It  has  been  stated 
already  that  the  members  of  this  series  act  as  stimulants  to  some  parts 
of  the  central  nervous  system,  and  a  possible  explanation  of  their 
antipyretic  action  would  be  an  increased  activity  of  the  temperature- 
controlling  centres.  It  has  been  shown  by  Harnack  that  several  central 
nervous  stimulants,  including  picrotoxin,  cause  a  fall  in  the  temperature 
in  this  way. 

Absorption  and  Distribution. — The  glucosides  of  this  series  are  peculiarly 
susceptible  to  destruction  by  the  ferments  of  the  alimentary  tract,  and 
there  is  no  doubt  that  a  part  of  those  taken  by  the  mouth  is  rendered  inert 
in  the  stomach  and  bowel.  After  a  dose  of  digitalis  leaves,  the  glucosides 
may  be  found  in  the  stomach  and  upper  part  of  small  intestine  biit 
none  reach  the  large  bowel  unchanged.  In  addition,  the  absori)tion  is 
very  slow  from  the  alimentary  tract;  it  follows  that  only  a  small  frac- 
tion of  the  drug  administered  by  the  mouth  ever  reaches  the  heart. 
On  hypodermic  injection,  the  glucosides  cause  marked  local  irritation, 
and  a  considerable  proportion  also  seems  to  undergo  decomposition,  for 
nnich  larger  quantities  are  required  to  induce  changes  in  the  heart  than 
are  necessary  by  intravenous  ai)plication.  After  the  ingestion  of  large 
amounts,  some  glucoside  is  said  to  have  b(>cn  found  in  the  liver,  but 
none  is  detected  in  the  heart  or  other  organs  and  the  blood  seems  to  be 


■THE  DIGITALIS  SERIES 


413 


free  from  it  soon  afterward.  Some  of  the  principles  have  been  foniid  in 
the  urine  and  faeces,  so  both  kidney  and  gut  share  in  the  excretion. 

Even  after  they  reach  the  blood  the  bodies  of  this  series  are  slow  in 
affecting  the  heart,  while  on  the  other  hand  their  action  is  very  pro- 
longed, the  heart  only  regaining  its  ordinary  rate  several  days  after  the 
drug  has  been  stopped.  If  the  dose  be  repeated,  the  action  therefore 
becomes  more  and  more  marked  (cumulative  action)  as  the  glucoside 
increases  in  concentration,  and  a  dose  which  improves  the  condition 
at  first,  may,  if  continued,  lead  to  the  second  phase  of  poisoning.  The 
different  glucosides  differ  in  the  duration  of  their  action;  thus  Hatcher 
estimates  that  seven-eighths  of  the  strophanthin  in  the  tissues  is 
eliminated  within  twenty-four  hours,  while  half  the  principles  of  digitalis 
remain  active  after  four  days.  It  is  still  undetermined  what  organs 
or  tissues  retain  the  glucosides  and  none  of  them  have  been  shown  to 
be  capable  of  destroying  them.  Straub  has  pointed  out  that  the  action 
of  strophanthin  on  the  frog's  heart  is  determined  by  the  concentration  in 
which  it  is  applied  and  not  by  the  total  amount  of  the  glucoside  supplied; 
for  example,  if  ten  drops  of  a  solution  circulating  through  the  excised 
heart  are  insufficient  to  bring  it  to  a  standstill,  one  hundred  drops  of 
the  same  solution  will  have  no  more  effect,  though  ten  drops  of  a  solution 
of  double  the  strength  will  arrest  it.  From  this  he  deduces  that  stro- 
phanthin is  not  taken  up  by  the  muscle  by  any  selective  action,  but  only 
penetrates  the  cells  in  the  concentration  of  the  solutions;  and  in  con- 
firmation of  this,  neither  Straub  nor  others  have  been  able  to  find  the 
glucoside  in  the  heart  muscle,  while  the  fluid  remaining  in  the  cavity 
has  lost  almost  none  of  its  toxic  action  if  applied  to  a  second  heart. 
From  the  minimal  amount  of  strophanthin  which  is  necessary  for  action 
on  the  heart  Straub  draws  the  conclusion  that  strophanthin  acts  by 
changing  the  membrane  of  the  heart  cells,  but  this  cannot  be  accepted 
as  established.  Some  others  of  the  series  have  been  found  to  the  taken 
up  in  larger  quantity  by  the  heart. 

Tolerance. — Some  species  of  animals  tolerate  much  larger  quantities 
of  the  digitalis  bodies  than  others.  For  example,  the  snake  and  toad 
are  not  poisoned  by  amounts  which  would  be  fatal  to  the  frog.  This 
arises  from  the  tissues  of  these  tolerant  animals  not  being  susceptible 
to  the  poisons,  and  not  from  any  difficulty  in  absorption  or  rapidity 
of  excretion;  for  the  isolated  hearts  in  these  animals  show  the  same 
refractory  behavior  as  the  intact  animal.  Among  the  mammals,  the 
rat's  heart  has  been  shown  to  be  much  less  susceptible  to  the  action 
of  these  bodies  than  the  rabbit's.  Tolerance  has  not  been  shown  to  be 
acquired  for  digitalis  and  its  allies  through  their  prolonged  use. 

The  digitalis  bodies  weaken  and  eventually  paralyze  the  Muscles  and  the 
terminations  of  the  peripheral  Nerves  of  the  frog.  For  this  purpose  it  has 
to  be  applied  in  quantities  which  would  at  once  stop  the  mammalian  heart, 
and  this  action  certainly  never  e\en  commences  in  warm-blooded  animals. 
Large  quantities  of  digitalis  are  said  to  act  on  the  unstriated  muscle  of  several 
organs,  such  as  the  stomach  and  uterus,  and  to  increase  their  movements,  and 
this  certainly  occurs  in  excised  organs  exposed  to  solutions  of  the  glucosides. 


414  SUBSTANCES  ACTING  AFTER  ABSORPTION 


Preparations. 

Digitalis  (U.  S.  P.).  Digitalis  Folia  {B.  P.),  foxglove,  the  leaves  of  Disitalis 
purpurea  collected  from  i)laiils  of  the  second  year's  growth.  0.0G5  G.  (1  gr.); 
15.  P.,  2-2  gr.  in  pill  form. 

Jnfusum  Digitalis,  U.  S.  P.,  S  c.c.  (2  fl.  drs.);   B.  P.,  2-4  fl.  drs. 

TiNCTURA  Digitalis  (U.  S.  P.,  B.  P.),  1  c.c.  (1.5  mins.);    B.  P.,  5-15  mins. 

"  Digitalifie"  of  commerce  varies  much  in  composition  and  in  dose,  some- 
times proving  entirely  inert,  while  at  other  times  it  has  proved  poisonous  in 
comparatively  small  quantities.  Cr,ystalline  digitaline  very  often  consists 
largely  of  digitonin,  which  is  quite  devoid  of  the  digitalin  action.  Other  pre- 
l)arations  seem  to  contain  much  digitophyllin.  Digitoxin  has  been  prescribed 
in  doses  of  i'.  mg.  {r\o  gi"-),  but  the  forms  at  present  on  the  market  vary  greatly 
in  strength.     Digolen  is  a  solution  of  impure  digitalein  from  the  leaves.    Dose, 

1  c.c.  or  15  mins.  Digipiiratum  is  said  to  contain  the  cardiac  glucosides  of  the 
leaves  in  combination  with  tannin  and  freed  from  most  of  the  inactive  con- 
stituents. Dose,  the  same  as  digitalis.  Digalen  seems  to  be  a  very  weak  prej^a- 
ration  and  has  no  advantage  over  the  ordinaiy  tincture.  Digipuratum  is 
very  carefulh'  standardized,  Ijut  is  not  otherwise  superior  to  the  powdered  leaf. 

The  tincture  and  infusion  are  the  most  commonl}'  used  preparations.  The 
powdered  leaves  maj^  be  given  in  the  form  of  pills.  The  preparations  ought 
to  be  freslil.y  made,  and  the  infusion  and  solutions  of  "digitaline"  and  digitoxin 
must  not  be  kept,  as  they  soon  decompose. 

Strophanthus  (U.  S.  P.),  Strophanthi  Semina  (B.  P.),  the  seeds  of  Stro- 
phanthus  Kombe,  0.065  G.  (1  gr.). 

TiNCTURA  Strophanthi  (U.  S.  P.,  B.P.),0.5c.c.  (8  mins  );  official  dose  (B.  P.), 
2-5  mins.;  effective  dose,  5-10  mins 

Strophanthinum  (U.  S.  P.),  the  glucoside  of  Strophanthus  Kombe,  varies 
in  composition  and  in  power.  Its  dose  is  given  as  0.3  mg.  (injj  gr.),  but  this  is 
(juite  devoid  of  action  when  given  by  the  mouth;  it  is  a  suitable  amount  for 
intravenous  injection,  though  many  prefer  to  inject  0.4-0.5  mg.  A  crystalline 
g-strophanthin  has  been  obtained  by  Thoms  from  Strophanthus  gratus  and  is 
a  definite  bod.y  with  a  dose  for  intravenous  injection  about  half  that  of  the 
official  strophanthin. 

Scilla  (IT.  S.  P.,  B.  P.),  squills,  the  bulb  of  Urginea  maritima  or  Urginea  Scilla, 
cut  into  thin  slices.    0.125  G.  (2  grs.)  in  pills. 

Acetum  Scilla;  (U.  S.  P.,  B.  P.),  1  c.c.  (15  mins.);  B.  P.,  5-15  mins. 

TiNCTURA  SciLLTE  (U.  S.  P.,  B.  P.),  1  C.C.  (15  mins.) ;   B.  P.,  5-15  mins. 

Syrupus  Scilue  (U.  S.  P.,  B.  P.),  2  c.c.  (30  mins.);  (B.  P.),  30-60  mins. 

Syrupus  Scill.e  Compositus  (U.  S.  P.),  containing  senega  and  tartar  emetic, 

2  c.c.  (30  mins.). 

Pilula  Ipecacuanh.e  cum  Scilla  (B.  P.),  contains  5  per  cent,  opium.    4- 

Sc[uills  is  often  j)rescribed  in  pill  form  as  a  diuretic;  as  an  expectorant  the 
syrup  is  more  often  used.  The  com]wund  syrup, 'IT.  S.  P.,  or  the  jiill  of  Ipecac 
and  Sfjuill,  B.  P.,  may  be  ordered  instead  of  a  cough  mixture,  as  they  contain 
the  chief  constituents  of  such  remedies. 

Scillotoxin,  etc.,  of  commerce  are  merely  purified  extracts  and  not  i)urc 
|)rincipl('s. 

Apocynum  (U.  S.  P.),  Canadian  hemp,  the  root  of  Apocynum  cannabinum. 

Flnidixlrdcbim  Apocyni  (U.  S.  P.),  1  c.c.  (15  mins.). 

Convallaria  iV.  S.  P.).  Lily  of  the  Valley,  the  rhizome  and  roots  of  Con- 
vallnria,  niajalis,  0.5  G.  (7\  grs.). 

Fliiidcxlnirtuni  Convallariir  (U.  S.  P.),  0.5  c.c.  (8  mins.). 

Euonymus  (T.  S.  P.),  Euonymi  Cortex  (B.  P.),  Wahoo,  the  bark  of  the 
root.s  of  Muonvnnis  atroijurpincus,  0.5  G.  (7.v  grs.). 

Exlmvlmn  Knoinjmi  (U.  S.  P.),  0. 125  G.  (2  grs.);  (B.  P.),  1-2  grs. 


THE  DiaiTAlAH  SERIES  415 

The  iiiiportaiice  of  this  group  in  therapeutics  is  so  great  that  it  is 
to  he  regretted  that  no  adequate  method  of  chemically  estimating  the 
content  of  active  principles  is  available.  For  the  crude  drugs  appear 
to  vary  in  activity  very  greatly,  and  even  when  the  attempt  is  made 
to  use  the  glucosides  themselves,  the  difficulty  in  their  isolation  and 
identification  leads  to  uncertainty  in  their  dosage.  There  has  there- 
fore been  introduced  (Houghton)  a  method  of  assaying  the  strength 
of  the  preparations  of  digitalis,  squills  and  strophanthus  according 
to  the  quantity  necessary  to  produce  changes  in  the  circulation.  As 
a  general  rule  the  smallest  quantity  which  is  sufficient  to  arrest  the 
frog's  heart  in  a  definite  time  has  been  taken  as  the  unit,  and  such 
standardized  preparations  are  now  available.  The  active  principles 
stand  in  no  less  need  of  being  assayed.  Only  by  using  these  stand- 
ardized preparations  can  there  be  any  certainty  that  the  patient  is 
receiving  a  imiform  dose  of  these  drugs  (Edmunds). 

Methods  of  Administration. — For  ordinary  purposes  the  members 
of  the  digitalis  group  are  given  by  the  mouth,  and  the  most  suitable 
preparations  are  the  three  tinctures  of  digitalis,  strophanthus,  and 
squills.  These  are  generally  given  alone  in  cases  of  heart  disease, 
and  it  is  of  importance  to  remember  that  they  do  not  maintain  their 
power  if  they  are  kept  diluted  with  water.  The  tinctures  may  best 
be  sent  out  undiluted  with  directions  to  take  the  requisite  dose  in  a 
wineglass  of  water.  The  best  results  are  often  obtained  from  larger 
doses  than  the  pharmacopoeias  admit;  thus  a  drachm  of  tincture 
of  digitalis  may  be  required  per  day.  The  tincture  of  strophanthus 
is  rather  stronger  than  the  tincture  of  digitalis  and  has  a  smaller  dose. 
The  tincture  of  squills  of  both  pharmacopoeias  should  be  given  in  twice 
the  pharmacopoeial  dose  to  elicit  the  same  effects  as  the  tincture  of 
digitalis.  Large  doses  of  these  preparations  are  not  always  necessary, 
but  there  is  no  question  that  in  many  instances  the  failure  of  digitalis 
to  relieve  symptoms  is  due  to  the  use  of  inadequate  doses.  The  action 
of  digitalis,  strophanthus,  and  squills  differs  very  little  when  they  are 
given  in  equivalent  doses;  tincture  of  digitalis  on  the  whole  is  the  most 
reliable. 

The  so-called  pure  principles  should  not  be  given  by  the  mouth; 
strophanthin,  the  only  one  of  them  recognized  by  the  pharmacopoeia, 
undergoes  decomposition  in  the  alimentary  tract,  especially  when  given 
in  pure  form.  No  preparation  can  be  injected  hypoderniically  in 
efficient  amount  owing  to  the  local  irritant  action,  and  though  intra- 
muscular injections  of  strophanthin  have  occasionally  been  made, 
they  also,  cause  much  pain  and  irritation.  In  emergencies  strophanthin 
may  be  injected  intravenously  in  sterilized  Ringer's  solution.  The 
injection  should  be  made  very  slowly;  not  more  than  0.5  mg.  (yio  Sr-) 
should  be  given  and  this  is  generally  dissolved  in  2-5  c.c.  The  injection 
is  not  repeated  within  twenty-four  hours  except  in  special  conditions 
and  after  careful  examination  of  the  patient. 

Therapeutic  Uses. — Digitalis  has  long  been  the  sheet-anchor  in  treat- 
ment of  diseases  of  the  heart,  but  little  was  done  to  elucidate  its  clinical 


4  Hi 


SUBSTANCES  ACTING  AFTER  ABSORPTION 


ai'tioii  until  tlie  last  few  years  (Mackenzie).  Much  still  remains  to 
be  investigated,  but  it  has  at  least  been  determined  that  it  is  much 
more  efficacious  in  certain  forms  of  cardiac  impairment  than  in  others. 
Its  most  remarkable  therapeutic  effects  are  seen  in  cases  of  Auricular 
fibrillation,  for  which  it  may  be  said  to  be  a  specific  comparable  only 
to  quinine  in  malaria.  In  auricular  fil)rillation,  the  impulses  arise 
in  different  parts  of  the  auricle  and  keep  that  chanil:)er  in  continual 
incoordinate  activity  which  prevents  its  emptying  its  contents  into  the 
ventricle.  The  multitudinous  impulses  generated  in  the  auricles  descend 
irregularly  to  the  ventricle,  which  resi)onds  with  a  rapid  beat  varying 
not  only  in  rhythm  but  also  in  strength;  many  of  the  contractions  are 
too  weak  to  expel  any  blood  into  the  aorta,  while  others  cause  large 
pulses,  and  these  are  intermixed  in  the  most  confused  fashion;  the 
pulse  is  thus  extremely  irregular  (Fig.  55).  This  irregular  heart  is  quite 
compatible  with  moderate  health  for  long  periods,  but  sooner  or  later 
the  signs  of  failing  circulation  appear,  the  pulse  becomes  alarmingly 

Fig.  55 


Pulse  tracings  in  a  case  of  auricular  fibrillation  in  man.  A,  before  treatment;  B, 
after  six  days'  treatment  with  tincture  of  digitalis  (60  mins.  each  day);  the  pulse  is 
slower  (62  beats  per  minute)  and  more  regular.  C,  after  ten  days'  treatment;  pulse,  41 
per  minute,  regular  (spontaneous  ventricular  rhythm).     (Windle.) 

rapid,  and  a  dangerous  condition  develops  quickly.  If  digitalis  is  now 
exhibited  in  full  doses,  these  symptoms  of  heart  failure  abate  rapidly, 
improvement  beginning  after  24-48  hours  and  the  danger  disai)i)eariiig 
in  a  few  days.  If  strophanthin  (yio  gr.)  is  injected  intravenously,  the 
improvement  begins  within  two  hours  and  is  marked  in  8-12  hours. 
In  each  case  the  pulse  falls  in  rate  and  this  slowing  proceeds  in  pro- 
])ortion  to  the  general  improvement  and  may  be  taken  as  a  measure 
of  it.  The  heart  may  be  slowed  from  130-150  per  minute  to  50-00 
in  the  course  of  a  few  hours,  and  at  the  same  time  the  beats  become 
stronger  and  more  equal  in  size  and  in  time  (Fig.  55). 

The  way  in  which  digitalis  effects  this  change  in  auricular  fibrillation 
is  still  ol)Scure,  and  it  is  unknown  whether  the  slowing  of  the  heart  is  the 
cause  of  the  improvement  or  whether  the  increased  strength  of  the  heart 
lead^  to  a  slower  rhythm.  The  auricles  continue  to  fibrillate  after  the 
pulse  is  slowed,  but  the  ventricle  responds  to  fewer  of  the  imi)ulscs 
emitted  b\  the  auricle,  either  l)ecause  fewer  of  them  reach  the  ventricle 


THE  DIGITALIS  SERIES 


417 


tliroiig-h  (lio;italis  lcssenin<^  the  conductivity  through  the  l)un(llc  of 
His,  or  because  the  ventricle  is  unable  to  respond  to  them  from  its  ex- 
citability being  reduced;  it  is  conceivable  that  the  latter  may  be  the 
result  of  the  direct  action  of  digitalis  on  the  ventricle,  or  that  it  may 
arise  indirectly  from  the  drug  increasing  the  strength  of  the  contractions 
and  thus  improving  the  nutrition  of  the  chamber. 

The  slowing  of  the  pulse  in  auricular  fibrillation  does  not  arise  from 
inhibitory  action,  for  it  is  not  prevented  by  atropine;  in  fact  when  a 
patient  is  under  digitalis  and  the  pulse  is  slowed,  the  inhibitory  mechan- 
ism is  less  active  than  before  treatment  when  the  pulse  was  rapid;  this 
is  shown  by  the  fact  that  paralysis  of  the  inhibition  by  atropine  does 
not  accelerate  the  heart  so  much  under  digitalis  in  these  cases  as  it  did 
before  treatment  was  begun.  The  specific  effect  of  digitalis  and  its 
allies  in  auricular  fibrillation  must  therefore  arise  from  the  muscular 
action  of  the  drug.  In  what  way  the  muscular  action  benefits  the  con- 
dition is  unknown,  for  it  is  not  possible  to  induce  the  same  effects  in 
animals  in  which  auricular  fibrillation  has  been  caused  experimentally. 
And  in  mammals  the  conduction  is  not  materially  lessened  by  digitalis 

Fig.  56 


-T^/ 


Tracing  of  the  radial  pulse  (below)  and  of  the  heart-apex  (above)  in  a  case  of  auricular 
fibrillation  treated  with  digitalis  tincture.  The  apex  tracing  shows  coupled  beats  (bigem- 
inus),  each  normal  contraction  being  followed  by  a  rapid  secondary  beat;  these  secondary 
beats  are  not  strong  enough  to  expel  blood  into  the  aorta  and  are  not  indicated  on  the 
radial  tracing.     (Windle.) 


if  the  vagus  action  is  excluded;  nor  is  any  marked  change  observed  in 
the  ventricular  excitability.  It  is  possible  that  the  nearest  analogy  to 
the  action  of  digitalis  in  auricular  fibrillation  in  man  is  offered  by  the 
frog,  in  which  the  conductivity  is  reduced  by  members  of  this  series  (p. 
399).  But,  again,  it  is  possible  that  the  apparent  change  in  conduc- 
tivity in  auricular  fibrillation  is  the  indirect  result  of  the  strengthened 
contractions.  The  blood-pressure  cannot  be  accurately  estimated  in 
auricular  fibrillation  owing  to  the  irregularity  of  the  pulse,  and  it  is 
therefore  unknown  whether  it  is  altered  under  treatment. 

Not  infrequently  in  this  condition  the  dose  has  to  be  very  large,  and 
if  it  be  continued  the  patient  suffers  from  nausea  and  vomiting.  Or 
the  pulse  may  fall  to  about  40  per  minute  (Fig.  55)  and  become  regular; 
the  ventricle  now  receives  no  impulses  from  the  auricle,  but  has 
developed  its  own  spontaneous  regular  rhythm.  More  frequently  the 
heart  develops  the  bigeminus  form  shown  in  Fig.  50,  in  which  each  full 
27 


418  SUBSTANCES  ACTING  AFTER  ABSORPTION 

beat  is  followed  very  quickly  by  a  secondary  one;  here  the  large  con- 
tractions arise  from  auricular  impulses,  but  the  excitability  of  the 
ventricle  has  risen  to  a  i)()int  at  which  it  also  discharges  impulses,  and 
this  coupled  rhythm  is  the  result.  These  are  all  indications  that  the 
drug  has  been  pushed  too  far,  and  they  all  disappear  when  the  dose  is 
reduced. 

In  some  cases  of  auricular  fibrillation  in  which  the  heart  is  not  much 
accelerated,  digitalis  has  no  such  striking  effect  though  improvement 
occurs  under  it.  And  when  fever  is  present  from  any  cause,  it  often 
fails  to  reduce  the  pulse  very  much.  The  tincture  may  be  given  up  to 
one  drachm  a  day  if  the  danger  is  not  pressing,  the  dose  being  reduced 
if  necessary  after  a  few  days.  In  greater  urgency,  strophanthin  (Ynir 
Y^-Q  gr.)  may  be  injected  intravenously,  and  the  treatment  contimied 
by  digitalis  by  the  mouth;  the  effects  of  the  strophanthin  will  be 
passing  off  before  the  digitalis  begins  to  act;  or  strophanthus  or  squills 
may  be  substituted  for  digitalis.  After  the  emergency  has  passed,  the 
dose  of  digitalis  necessary  to  keep  the  pulse  fairly  low  is  found  by 
gradually  reducing  the  daily  dose,  and  this  amount  may  have  to  be 
taken  for  a  long  time  or  even  taken  at  intervals  throughout  life,  for 
the  underlying  condition  of  auricular  fibrillation  persists  in  spite  of  all 
treatment. 

In  Other  Forms  of  Heart  Disease  the  effects  of  digitalis  are  less  spec- 
tacular than  in  auricular  fibrillation,  and  although  improvement  un- 
doubtedly results  from  the  treatment,  there  is  no  such  guide  as  is  offered 
l)y  the  slowing  of  the  pulse  in  fibrillation.  It  is  therefore  not  always 
easy  to  determine' how  far  the  improvement  is  to  be  attributed  to  the 
digitalis  and  how  far  to  such  auxiliaries  as  rest  and  general  treatment. 
Such  measurable  symptoms  are  often  presented  as  dropsy,  however, 
and  the  fall  in  weight  from  diuresis  under  digitalis  is  as  significant 
evidence  as  the  fall  in  pulse  rate  in  fibrillation.  Few  accurate  observa- 
tions arc  as  yet  available  except  in  auricular  fil)rillation,  but  they  suffice 
to  show  that  the  beneficial  action  of  digitalis  is  not  confined  to  this 
special  form  of  heart  disease.  In  general  terms  it  may  be  said  that 
improvement  is  seen  in  a  large  number  of  conditions  in  which  the 
efficiency  of  the  heart  is  impaired  and  the  blood  is  no  longer  pumped 
from  the  venous  reservoirs  to  the  arteries  in  adccpiatc  amount.  The 
deficient  circulation  no  longer  suffices  to  maintain  the  nutrition  of  the 
tissues,  including  the  heart,  and  dilatation  of  the  heart  chambers, 
congestion  of  the  lungs,  (edema  and  dropsy  follow;  the  kidneys  and 
other  organs  become  overfilled  with  venous  blood  and  the  whole  economy 
is  thrown  into  disorder.  The  treatment  obviously  comprises  rest  to 
relieve  the  strained  organs,  along  with  some  member  of  this  series  to 
increase  the  strength  of  the  contractions  of  the  heart  and  thus  to  com- 
]>ensatc  for  the  disorders  which  are  the  primary  cause  of  the  condition. 
AihI  under  digitalis  such  improvement  occurs;  the  congestion  disappears, 
the  kidneys  secrete  more  rapidly  and  drain  off  the  accumulations  of 
fluid  in  the  tissues  and  cavities  of  the  body.  The  heart  itself  is  better 
nourished   through  the  acceleration  of  the   bloodstream,   and   is   now 


THE  DIGITALIS  SERIES  419 

al)le  to  hypertrophy  in  order  to  meet  the  strain  thrown  upon  it  by  such 
damages  as  destruction  of  the  valves.  The  only  action  of  the  drug  which 
seems  to  he  necessary  for  this  pupose  is  its  power  to  increase  the  strength 
of  the  contraction;  liow  far  the  contractions  are  actually  strengthened 
in  these  cases  cannot  be  determined,  as  no  method  is  known  by  which 
this  can  be  measured.  It  is  possible  that  the  dilatation  of  the  heart 
may  be  reduced  by  the  muscular  action,  as  occurs  in  animal  experiments, 
but  here  again  it  is  difficult  to  measure  the  improvement  in  man.  But 
if  such  an  effect  follows  either  from  the  direct  action  of  the  drug  or  as  a 
result  of  the  improved  nutrition,  it  may  tend  to  compensate  for  the 
imperfection  of  a  diseased  valve  by  narrowing  the  orifice  during  diastole. 
And  as  the  auricle  is  improved  by  digitalis,  it  may  empty  itself  more 
completely  into  the  ventricle  and  perhaps  relieve  the  venous  stasis  in 
this  way.  The  increased  contraction  of  the  papillary  muscles  may  also 
aid  in  the  therapeutic  effect  by  closing  the  valves  more  completely. 
The  improvement  in  these  cases  is  thus  readily  intelligible,  but  further 
observation  is  required  before  the  details  of  the  action  can  be  established. 
In  some  of  these  patients  digitalis  slows  the  pulse,  but  this  is  not  an 
essential  factor  in  the  improvement,  for  the  improvement  is  not  more 
rapid  than  in  similar  instances  in  which  no  such  change  occurs. 

The  beneficial  action  of  digitalis  is  generally  stated  to  be  more  obvious 
in  disease  of  the  mitral  than  in  that  of  the  aortic  valves.  This  view 
may  have  arisen  from  the  fact  that  auricular  fibrillation  is  often  accom- 
panied by  mitral  disease.  In  some  cases  of  aortic  valve  failure  digitalis 
is  undoubtedly  of  value,  but  there  seems  some  reason  to  doubt  whether 
it  is  as  often  efficacious  as  in  mitral  disease  even  when  the  fibrillation 
cases  are  excluded.  It  is  sometimes  stated  that  in  aortic  regurgitation 
digitalis  is  dangerous  owing  to  its  prolonging  the  diastolic  interval  and 
thus  allowing  more  time  for  the  blood  to  flow  back  from  the  aorta.  In 
very  many  cases,  however,  the  heart  is  not  slowed  and  there  is  thus  no 
prolongation  of  the  diastole;  and  it  seems  unlikely  that  even  when 
slowing  occurs  it  is  sufficient  to  counterbalance  the  benefits  of  the 
stronger  contraction  in  systole.  In. experimental  lesions  of  the  aortic 
valves  in  animals,  digitalis  is  found  to  improve  the  efficiency  of  the 
heart  and  a  smaller  mortality  occurs  in  animals  under  treatment  than 
in  the  controls. 

On  the  right  side  of  the  heart  the  same  action  occurs  as  on  the  left, 
and  in  dilatation  of  the  right  heart,  such  as  occurs  in  some  pulmonary 
diseases,  digitalis  and  its  allies  are  beneficial,  apparently  by  increasing 
the  strength  of  the  ventricular  contraction. 

In  the  majority  of  these  non-fibrillating  cases  the  pulse  is  not  slowed 
more  than  can  be  accounted  for  by  the  rest  and  general  treatment; 
in  other  words  the  quantity  requisite  to  improve  the  condition  of  the 
heart  is  too  small  to  stimulate  the  vagus  centre.  In  a  certain  proportion, 
however,  distinct  slowing  is  observed  as  the  heart  comes  under  the 
influence  of  the  drug,  and,  as  this  generally  disappears  under  atropine, 
it  is  obviously  inhibitory  in  character  in  most  cases  and  thus  different 
from  the  slowing  seen  under  digitalis  in  auricular  fibrillation. 


-120 


.SUnSTAM'ES   AVTlSd   AFTER   AliSOlil'TlON 


As  regards  the  irregularitii^s  in  tliese  noii-fihrillating  cases,  there  is 
no  reason  to  believe  that  digitalis  has  anv  direct  action  on  them,  though 


Fig.  57 


The  lowest  tracing  is  given  by  the  radial  artery,  the  next  by  the  jugular  vein,  while 
the  time  is  given  in  one-fifth  seconds  above.  In  the  jugular  tracing  a,  a',  indicate  the 
auricular  contractions.  In  the  radial  tracing,  the  large  beats  are  the  normal  pulse  waves; 
at  X,  a  premature,  weak  contraction  of  the  ventricle  occurs  (extrasystole),  arising  from  the 
increased  spontaneous  irritability  of  that  chamber  induced  by  digitalis.  The  larger 
size  of  a'  is  due  to  the  fact  that  when  the  auricle  contracts  the  ventricle  is  already  in 
systole,  and  therefore  cannot  receive  the  auricular  contents,  which  are  thus  sent  back 
into  the  veins,  producing  this  larger  wave.     (Mackenzie.) 

Fig.  58 


Jug.  and  Car. 


Tracings  from  the  radial  artery  and  the  jugular  vein  in  a  case  of  heart-disease  treated 
with  digitalis  in  large  doses.  The  waves  a,  a'  on  the  jugular  tracing  indicate  the 
auricular  contractions  and  are  seen  to  be  perfectly  regular  in  rhythm  throughout;  the 
auricle  is,  therefore,  beating  regularly.  The  radial  pulse  intermits  at  intervals,  showing 
that  the  ventricle  has  not  responded  to  the  impulses  which  in  the  auricle  gave  rise  to 
the  contractions  indicated  by  a'.     (Mackenzie.) 


Fig.  5'J 


Bad 


Slowing  of  the  pulse  due  to  digitalis  depressing  conductivity,  so  that  the  ventricle  fails 
to  respond  to  every  second  stimulus  from  the  auricle.  While  the  ventricle  contracted 
lorly-i'itrlit  tiinrs  |)cr  iniiuilc,  the  auricle  coiitraclcil  ninety-six  times.     (Mackenzie.) 

they   nia\-  disappear  in   the  course  of  treatment   as  the  result   oi'  the 
iini)ro\'ed  nutrition  of  the  heart. 


THE  DIGITALIS  SERIES  421 

On  the  other  hand,  the  use  of  (HgitaHs  sometimes  ji;ives  rise  to  irreji;u- 
hirities,  and  the  eharacter  of  these  has  reeeived  a  good  deal  of  attention 
of  hite  years.  The  first  form  arises  from  the  museular  action,  which 
may  increase  the  excitabihty  of  the  ventricle  or  auricle  so  much  that 
spontaneous  beats  (extrasystoles)  arise  (Fig.  57).  These  are  not  of 
great  importance,  but  the  heart  should  be  carefully  watched  and,  if 
possible,  the  dose  should  be  reduced.  Other  forms  arise  from  the 
stimulation  of  the  inhibitory  mechanism,  which,  as  has  been  stated, 
occurs  in  a  certain  proportion  of  patients  and  which  may  become  very 
marked.  This  vagus  stimulation  merely  slows  the  heart  in  the  milder 
forms,  the  beats  remaining  regular.  Or  the  slowing  which  occurs  in 
normal  people  in  correspondence  with  the  breathing,  may  be  exaggerated, 
and  the  slow,  powerful  contractions  cause  an  unpleasant  sensation  in 
the  chest.  This  occurs  when  the  vagus  is  strongly  stimulated  from  any 
cause  and  is  not  peculiar  to  digitalis.  When  this  form  of  irregularity 
sets  in,  the  dose  should  be  reduced  or  the  drug  omitted  altogether  for 
a  few  days.  Not  infrequently,  a  less  obvious  vagus  eflFect  causes  irregu- 
larity under  digitalis;  the  passage  of  impulses  from  the  auricle  to  the 
ventricle  is  retarded  or  entirely  arrested,  from  the  conduction  through 
the  connecting  fibres  being  reduced.  Before  the  treatment  the  fibres 
were  able  to  conduct  all  the  impulses  from  the  auricle  to  the  ventricle, 
though  perhaps  they  passed  more  slowly  than  in  quite  normal  hearts. 
But  now  an  occasional  impulse  fails  to  pass,  or  perhaps  only  one  of  two 
impulses  passes  to  the  ventricle.  When  an  impulse  fails  to  reach  it, 
the  ventricle  remains  in  diastole  (dropped  beat)  (Fig.  58),  and  when 
only  one-half  the  impulses  pass  to  it,  the  rhythm  of  the  ventricle  is 
only  half  that  of  the  auricle  (half-rhythm)  (Fig.  59).  Or  the  block 
may  be  complete,  no  impulses  passing  through  the  fibres  at  all,  and  in 
this  case  the  ventricle  takes  up  its  own  spontaneous  rhythm  (heart- 
block).  Another  form  of  block  may  occur  between  the  sinus  and  the 
auricle  (sino-auricular  block),  and  both  auricle  and  ventricle  now  intermit 
a  contraction  at  variable  intervals.  In  all  these  forms  digitalis  interferes 
with  the  passage  of  impulses  from  the  auricle  to  the  ventricle,  or  from 
the  sinus  to  the  auricle,  by  stimulating  the  inhibitory  mechanism,  which 
lessens  the  conductivity  of  the  connecting  fibres.  The  irregularity 
therefore  disappears  under  atropine  which  paralyzes  the  inhibitory 
mechanism.  But  in  rarer  cases  the  digitalis  heart-block  does  not  arise 
from  the  inhibitory  stimulation  but  from  some  obscure  direct  action  on 
the  conducting  fibres,  and  this  form  of  block  which  may  be  sino-auricular 
or  auriculo-ventricular,  is  not  relieved  by  atropine.  The  inhibitory 
block  under  digitalis  is  similar  to  that  seen  in  experiments  on  mammals 
in  the  second  stage,  while  the  rarer  block  from  direct  action  reminds 
one  of  the  lessened  conductivity  seen  in  the  frog,  and  suggests  that 
the  slowing  seen  in  auricular  fibrillation  may  occur  from  a  similar 
action.  When  heart-block  occurs  under  digitalis,  the  treatment  should 
be  abandoned  or  the  dose  reduced.  Slight  slowing  in  non-fibrillating 
cases  does  not  indicate  a  change  of  treatment.  Another  form  of  irreg- 
ularity which  sometimes  appears  under  digitalis   is  known   as   i)ulsys 


422  SUBSTANCES  ACTING  AFTER  ABSORPTION 

alternaiis  (Fig.  60),  and  is  marked  by  an  alternation  of  strong  and 
weak  beats  of  the  radial  pulse.  This  generally  indicates  impaired  con- 
tractility of  the  ventricular  wall,  and  its  occurrence  under  digitalis  has 
not  as  yet  received  adequate  explanation.  Finally  a  number  of  cases 
have  been  reported,  in  which  a  regular  heart  developed  auricular  fibril- 
lation under  digitalis  for  a  longer  or  shorter  period.  No  satisfactory 
explanation  of  this  phenomenon  has  been  given,  except  that  the  auricular 
excitability  was  abnormally  augmented  l)y  the  drug.  The  treatment 
has  to  be  stopped  immediately  and  the  heart  soon  returns  to  its  normal 

sequence. 

Fig.  60 


Typical  pulsus  allcrnans  due  to  digitalis.     Each  pulse  period  is  of  the  same  duration 
while  the  size  of  the  beat  varies  rhythmically,     (Mackenzie.) 

In  numerous  Acute  Febrile  Conditions  the  heart  becomes  affected, 
possibly  in  part  by  the  high  temperature,  but  largely  from  the  toxic 
products  circulating  in  the  blood.  The  chief  cardiac  symptoms  are 
dilatation  with  a  weak  systole  and  a  small  "fluttering"  pulse.  In  these 
cases  digitalis  and  other  similar  drugs  may  be  of  great  service  in  slowing 
the  accelerated  heart  and  in  increasing  the  extent  of  systole,  and  thus 
improving  the  general  circulation.  In  pneumonia  more  especially, 
great  improvement  is  often  seen  after  digitalis.  In  this  disease,  besides 
the  toxic  action  on  the  heart,  there  may  be  present  more  or  less  obstruc- 
tion of  the  pulmonary  vessels  through  pressure,  resulting  in  overwork 
and  dilatation  of  the  right  heart.  The  routine  treatment  of  pneumonia 
with  digitalis  is  often  recommended,  but  is  to  be  deprecated  on  the 
general  principle  that  a  drug  is  not  to  be  prescribed  until  some  special 
indication  for  it  appears;  unless  distinct  evidence  of  circulatory  dis- 
turbance is  ])resent,  digitalis  ought  to  be  withheld. 

In  acute  fevers  the  inhibitory  mechanism  is  often  less  irritable  tluni 
normally,  and  the  activity  of  the  drug  must  not  be  estimated  by  the 
slowness  of  the  pulse. 

In  some  aft'ections  of  the  heart,  such  as  very  extensive  fibrous  or 
fatty  degeneration,  digitalis  often  is  of  little  or  no  service,  and  some 
aiitiiorities  deprecate  its  use,  chiefly  on  the  erroneous  view  that  it  may 
raise  the  blood-pressure  and  increase  the  resistance  against  which  the 
heart  has  to  work.  In  the  light  of  recent  work  this  argument  falls  to  the 
ground  and  the  general  view  may  be  stated  that  while  digitalis  may  fail 
to  iini)rove  these  cases,  it  has  no  deleterious  elfect  on  tluMii.  In  other 
cases,  while  the  condition  of  the  heart  is  eminently  suitable  for  digitalis 
treatment,  disease  of  other  parts  of  the  body,  sucli  as  extensive  arterial 
degeneration,  is  said  to  ])reclude  its  use  on  account  of  the  danger  of 
rupture  of  the  arterial  walls.     And  many  substitute  strophanthus  for 


THE  DIGITALIS  SERIES  423 

it  in  these  cases  in  the  behef  that  there  is  then  less  risk  of  the  blood- 
pressure  rising  to  a  dangerous  height.  But  as  a  matter  of  fact  there  is 
no  reason  to  anticipate  any  extensive  rise  of  blood-pressure  under  either 
digitalis  or  strophanthus,  and  the  apprehension  is  thus  groundless.  The 
same  may  be  said  of  the  supposed  danger  of  digitalis  in  the  high  blood- 
pressure  of  renal  and  arterial  disease.  A  high  blood-pressure  ought 
not  to  be  regarded  as  definitely  contra-indicating  the  use  of  digitalis 
or  its  allies,  for  excellent  results  often  follow  its  exhibition  in  these  cases, 
provided  the  special  indications  for  digitalis  are  presented  in  venous 
stasis,  oedema,  or  deficient  urine.  In  these  cases  the  high  pressure 
presumably  arises  from  excessive  activity  of  the  vaso-constrictor  centre 
inducing  mesenteric  constriction  in  an  attempt  to  maintain  the  blood 
supply  to  the  brain;  this  involves  an  abnormal  resistance  to  the  circula- 
tion and  imperfect  nutrition  of  various  organs.  Digitalis  by  increasing 
the  efficiency  of  the  heart  improves  the  blood  supply  of  the  brain,  and  the 
activity  of  the  vaso-constructor  centre  is  abated,  leading  to  a  more 
normal  state  of  the  circulation  and  often  to  a  lower  arterial  tension. 

Valvular  disease  is  not  in  itself  an  indication  for  digitalis,  for  the 
heart  tends  to  undergo  compensatory  hypertrophy  in  favorable  condi- 
tions without  the  use  of  any  drug  whatever,  and  digitalis  is  indicated 
only  when  no  such  compensation  occurs.  At  the  same  time  hyper- 
trophy of  the  heart  is  not  a  contra-indication,  as  is  often  stated,  for  a 
special  strain  may  cause  excessive  dilatation  in  a  hypertrophied  heart, 
and  digitalis  may  be  necessary  until  a  second  hypertrophy  has  occurred 
and  restored  the  equilibrium  once  more. 

The  diuretic  action  of  digitalis  is  not  advised  except  where  other 
indications  than  a  diminution  of  the  renal  secretion  are  present,  for  in 
ordinary  cases  it  has  much  less  effect  than  caffeine  and  other  diuretics. 
If  the  anuria  be  secondary  to  disturbances  of  the  circulation,  however, 
digitalis  is  the  diuretic  par  excellence  and  cannot  be  replaced  by  any 
of  the  ordinary  means  of  promoting  the  urinary  secretion,  although 
they  may  advantageously  be  combined  with  it.  Squills  is  more  fre- 
quently used  as  a  diuretic  than  digitalis,  and  it  seems  probable  that  in 
addition  to  its  action  on  the  heart  and  circulation,  it  exercises  some 
direct  stimulant  influence  on  the  renal  epithelium.  Squills  and  digitalis 
are  often  prescribed  together,  where  large  accumulations  of  fluid  have 
to  be  removed.  A  famous  pill  used  in  these  cases  contains  a  grain  each 
of  digitalis,  squills,  and  calomel. 

Several  of  these  drugs  are  of  considerable  benefit  in  pulmonary 
diseases  accompanied  by  cough.  Thus  in  bronchitis,  more  especially 
in  cases  of  old  standing,  the  addition  of  squills  to  an  "expectorant 
mixture"  is  often  followed  by  the  most  satisfactory  results.  The 
action  here  is  probably  twofold.  In  the  first  place,  the  right  heart 
may  be  dilated  owing  to  the  frequent  strain  put  on  it  by  coughing, 
and  squills  remedies  this  condition  by  its  usual  cardiac  action.  In 
the  second  place,  all  these  drugs  possess  to  a  certain  extent  emetic 
properties,  and  thus  cause  an  increase  in  the  bronchial  secretion,  and 
render  the  sputum  less  tenacious  and  more  easily  expectorated.     The 


424  SUBSTANCES  ACTING  AFTER  ABSORPTION 

addition  of  squills  has  the  same  effect  as  the  prescription  of  ipecacuanha, 
along  with  the  further  action  on  the  heart. 

l)ifi;italis  is  sometimes  prescribed  to  stop  luemorrhages,  but  even 
when  it  constricts  the  vessels  it  accelerates  the  flow  through  them,  and, 
as  in  the  case  of  other  luemostatics,  the  benefits  arising  from  the  treat- 
ment are  problematical.  In  the  circulatory  weakness  following  severe 
luemorrhage  and  shock  the  effects  of  this  series  would  seem  to  be 
indicated,  were  it  possible  to  elicit  their  action  sufficiently  rapidly. 
I'nfortunately  many  hours  generally  elapse  before  the  lieart  and  vessels 
are  affected,  when  they  are  exhibited  by  the  mouth.  These  con- 
ditions are  generally  treated  by  more  rapidly  acting  measures,  such 
as  the  intravenous  injection  of  salt  solution;  the  effects  of  this  treat- 
ment are  maintained  much  longer  if  a  small  quantity  of  strophanthin 
(t5  0  gr.)  is  added  to  the  salt  solution.  This  dose  must  not  be  rejieated 
within  twenty-four  hours. 

Squills  was  at  one  time  used  as  an  emetic,  but  this  cannot  be  recom- 
mended, owing  to  the  danger  of  its  absorption.  Euonymus  has  been 
emjiloyed  as  a  purgative  more  frequently  than  as   a  cardiac  remedy. 

Cumulative  Action. — Digitalis  is  often  given  in  insufficient  amount 
from  a  dread  that  it  may  cause  serious  results  through  its  cumulative 
action.  This  apprehension  does  not  seem  to  exist  so  much  in  regard  to 
strophanthus  and  squills,  though  these  appear  to  have  no  less  tendency 
to  induce  cumulative  effects  when  they  are  given  in  sufficient  doses. 
As  a  general  rule  no  effects  are  noted  for  one  or  two  days  after  the 
exhibition  of  drugs  of  this  series.  Improvement  then  begins  if  the  case 
is  suitable  and  the  dose  adequate,  and  steady  progress  may  be  made 
for  some  time.  If  large  doses  are  being  given,  the  symptoms  of  excessive 
action  may  set  in  suddenly — the  pulse  becomes  alarmingly  slow  and 
irregular,  the  patient  complains  of  weakness  and  faintness,  nausea,  and 
occasionally  vomiting;  in  fact  the  symptoms  of  the  second  stage  set  in. 
This  is  known  as  cumulative  action,  and  is  probably  due  to  irregularities 
in  the  absorption  and  excretion  or  destruction  of  the  poison.  It  is 
known  that  the  absorption  is  slow,  for  12-3G  hours  may  elapse  before 
any  effects  follow  the  exhibition  of  the  drug.  On  the  other  hand,  the 
excretion  or  destruction  is  equally  slow,  for  the  action  sometimes  lasts 
for  several  days  after  it  has  l)een  discontinued.  If  then  anytliing 
happens  to  disturb  the  equilibrium  of  absorption  and  excretion,  if,  for 
example,  the  excretion  is  slower  than  usual,  or  if  any  irritation  of  the 
stomach  and  intestines  causes  a  more  rapid  absorption,  the  drug  ac- 
cumulates in  the  blood,  and  the  same  effect  is  produced  as  if  a  poisonous 
dose  had  been  administered.  The  fear  of  this  condition  is  much  ex- 
aggerated, for  the  symptoms  disappear  in  a  few  hours  if  the  drug  is 
omitted.  And  they  may  generally  be  avoided  altogether  if  a  close 
watch  is  kept  on  the  pulse,  and  the  tlose  is  reduced  as  soon  as  it  becomes 
very  slow  or  at  the  first  appc^arance  of  headache,  nausea,  or  loss  of 
appetite.  All  of  the  digitalis  series  hiterto  examined  i)rove  to  be  cumu- 
lative in  their  action,  but  some  of  them,  notably  digitoxin,  are  nuich 
more  dangerous  than  others.    In  fact,  according  to  Fraenkcl,  digitoxin 


ACONITINE 


425 


can  only  be  used  safely  in  doses  which  induce  no  changes  in  the  i)nlse 
for  several  days,  for  if  the  ])ulse  be  slowed  by  a  single  dose,  its  repetition 
within  twenty-four  hours  induces  severe  poisoning.  The  symi)toms  of 
cumulative  action  under  digitalis,  strophanthus,  and  squills  are  very 
similar;  there  is  perhaps  more  tendency  to  diarrhoea  under  the  two 
last  than  under  digitalis. 

Bibliography. 

Boehm.     Pfliiger's  Arch.  f.  d.  ges.  Physiol.,  v,  p.  153. 
Ciu^^  Schmiedeberg.     Arch.  f.  exp.  Path.  u.  Pharm.,  xvi,  p.  149. 

Francois-Franck.     Clinique  medicale  de  la  Charite.    Paris,  1S94,  p.  549. 

Cushny.     Journ.  of  Exp.  Med.,  ii,  p.  233. 

Marshall.     Journ.  of  Physiol.,  xxii,  p.  1. 

Pfaff.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxii,  p.  1. 

Klingenberg.     Ibid.,  xxxiii,  p.  353. 

Fraser.     Trans.  Roy.  Soc.  Edinburgh,  1890  and  1891.    (Strophanthus.) 

Fraser  and  Tillie.     Arch,  internat.  de  Pharmacodyn.,  v,  p.  349.     (Acokanthera.) 
.,'  Edmunds.     Amer.  Journ.  of  Phys.,  xviii,  p.  129.     Hygienic  Laboratory,  Washington, 
Bull.  No.  48. 

Lewin.     Virchow's  Arch.,  cxxxiv,  p.  231;    cxxxvi,  p.  83;    cxxxviii,  p.  283. 
Qij-'^^  Kiliani.     Arch,  der  Pharmacie,  1892-1899. 

~    Fraenkel.     Arch.  f.  exp.  Path.  u.  Pharm.,  xl,  p.  40;    li,  p.  84;    Ivii,  pp.  79,  123,  131. 

Straub.     Ibid,  xlv,  p.  317;   Ixxi,  p.  139.     Biochem.  Zeitschr.,  xxviii,  p.  392. 

Griinwald,  Gros,  Weizsdcker,  Holste.    Arch.  f.  exp.  Path,  u.  Pharm.,  Ixviii,  p.  231;  Ixxi, 
p.  364;  Ixxii,  pp.  282,  347;  Ixx,  p.  435. 

Braun  u.  Mager.     Sitzungsb.  d.  Wiener  Akad.  Math,  naturwissen.  CI.,  cviii,  iii,  p.  471. 

Faust.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlix,  p.  1;    xlviii,  p.  272. 

Gottlieb  and  Magnus.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlvii,  p.  135;  xlviii,  p.  262;   li,  p.  30. 

Rothberger  u.  Winterberg.     Pfluger's  Arch.,  cl,  p.  217. 

Gumi.     Journ.  of  Pharmacology,  iv,  p.  225. 

Sluytermann.     Zeitschr.  f.  Biol.,  Ivii. 

Kasztan,  Fahrenkamp.     Arch.  f.  exp.  Path.  u.  Pharm.,  Ixiii,  p.  405;  Ixv,  p.  367. 
■Hatcher  and  Eggleston.     Journ.  of  Pharmacol.,  iv,  p.  113. 

Hatcher.     Journ.  Amer.  Med.  Assoc,  1910,  ii,  p.  1697. 

Clark.     Journ.  of  Pharmacol.,  iv,  p.  399. 

Janeway,  Gottlieb,  etc.     Seventeenth  International   Med.   Congress,   Therap.   Section, 
London, 1913. 

Dale  and  Laidlaw.     Heart,  i,  p.  138.     (Apocynum.) 

Mackenzie.     Heart,  ii,  p.  273. 

Cushny,  Marris,  and  Silberberg.     Heart,  iv,  p.  33. 


XXI.    ACONITINE. 

This  series  embraces  a  number  of  alkaloids,  which  resemble  each 
other  closely  in  their  chemical  and  pharmacological  properties.  Some 
of  them  which  were  formerly  believed  to  be  perfectly  distinct  are  now 
said  to  be  identical,  and  it  is  not  improbable  that  future  investigation 
will  still  further  reduce  the  numbers  of  the  group. 

These  alkaloids  are  found  in  a  number  of  species  of  the  Aconitum 
genus,  the  best  known  of  which  are  Aconitum  Napellus,  containing 
Aconitine  (C34H47NOU),  Aconitum  ferox,  Pseudaconitine  (C36H49NO12), 
and  Aconitum  Japonicmii,  Ja-paconitine  (C34H49NOii). 

When  aqueous  solutions  of  these  alkaloids  are  heated,  they  are  broken  up 
into  one  or  more  acids  and  simpler  bases;  aconitine  forms  acetic  and  benzoic 
acids  and  Aconine,  so  that  aconitine  is  acetyl-benzoyl-aconine.    Pseudaconitine 


426  SUBSTANCES  ACTING  AFTER  ABSORPTION 

forms  Pseudaconine,  and  Japaconitine  Japaconine  in  the  same  way.  These 
decomposition  products  are  found  in  the  plant  and  in  the  ordinarj'^  preparations, 
so  that  their  toxicity  varies  very  considerably. 

Another  alkaloid  which  resembles  aconitine  closely  in  its  pharmacological 
action,  but  which  is  less  known,  is  Delphinine.  It  is  found  in  stavesacre  (Del- 
phinium Staphisagria),  along  with  a  number  of  other  bases,  which  may  be  the 
products  of  its  decomposition. 

The  sj'mptoms  caused  by  aconitine,  pseudaconitine,  japaconitine,  and  del- 
phinine are  veiy  similar,  differing  mainly  in  degree  and  not  in  kind.  Pseuda- 
conitine is  more  poisonous  than  japaconitine  which  in  turn  is  shghtly  more 
active  than  aconitine.    Delphinine  is  much  less  poisonous. 

Symptoms. — After  very  large  quantities  of  aconitine  death  may  result 
instantaneously,  apparently  from  simultaneous  failure  of  the  heart  and 
central  nervous  system. 

If  smaller  quantities  be  swallowed,  there  is  noted,  after  the  ordi- 
nary bitter  taste  of  the  alkaloid,  a  feeling  of  warmth  in  the  mouth  and 
throat,  which,  agreeable  at  first,  soon  becomes  prickling  and  tingling, 
and  extends  to  the  stomach  and  eventually  to  the  skin.  This  is 
accompanied  by  a  profuse  flow  of  saliva  and  often  by  vomiting.  The 
pulse  is  very  slow  and  ma}'  be  irregular,  and  later  becomes  weak  and 
imperceptible,  when  symptoms  of  collapse  appear.  The  respiration 
is  slow  and  labored,  and  great  muscular  weakness  is  complained  of. 
After  a  time  the  smarting  and  tingling  of  the  skin  are  no  longer  felt, 
and  on  examination  the  cutaneous  sensibility  is  found  to  be  much 
reduced.  The  intelligence  remains  unimpaired  to  the  last  in  many 
cases,  although  unconsciousness  sometimes  occurs,  and  death  is  gener- 
ally, but  not  invariably,  preceded  by  convulsions.  The  pupil  is  un- 
affected except  when  convulsions  supervene,  when  it  is  dilated.  The 
prickling  of  the  throat  and  skin  is  the  most  characteristic  symptom, 
and  is  practically  diagnostic  in  cases  of  poisoning,  no  other  drug  except- 
ing veratrine  having  this  eft'ect.  Death  is  sometimes  due  to  paralysis 
of  the  respiratory  centre  from  the  direct  action  of  the  poison,  but  in 
other  cases  the  heart  fails  before  the  respiration. 

In  small  doses  aconitine  induces  tingling  of  the  lips,  tongue  and 
throat,  which  is  followed  by  some  nausea  and  a  feeling  of  weakness  and 
depression.    The  heart  is  generally  accelerated  from  the  nausea. 

Action. — The  prickling,  tingling  sensation  is  due  to  an  afl'ection  of 
the  Terminal  Organs  of  the  Sensory  Nerves,  as  is  shown  by  its  appearing 
first  at  the  point  of  application  of  the  drug.  Thus,  when  aconitine  is 
swallowed,  the  prickling  and  warmth  is  felt  in  the  lips,  tongue  and 
Uiroat,  and  after  small  doses  may  be  confined  to  these  parts,  while  if 
an  ointment  containing  aconitine  be  rubbed  on  the  skin,  the  same  sen- 
sation is  induced  locally.  But  no  redness  or  swelling  of  the  skin  is 
induced,  nor  are  blisters  formed,  so  that  aconitine  differs  entirely 
from  the  class  of  skin  irritants  (page  72).  It  evidently  acts  by  stimu- 
lating the  terminations  of  the  sensory  nerves,  more  especially  those  of 
conunon  sensation,  while  the  other  sensory  end  organs  have  not  been 
shown  to  be  invohed.  Thus,  apart  from  the  bitter  taste  which  it 
possesses  in  coinnion   with  all  alkaloids,  aconitine  has  no  ell'ect   upon 


ACONITINE  427 

the  taste  organs  during  this  stage.  The  stimulation  afterward  passes 
into  depression,  which  induces  a  sense  of  numbness  at  the  point  of 
apphcation,  and  in  cases  of  poisoning,  in  all  the  surfaces  of  the  body. 
The  taste  nerves  seem  to  be  involved  in  this  effect,  if  Laborde's  state- 
ment be  correct  that  sweet  substances  have  no  taste  after  aconitine. 
The  irritation  of  the  sensory  terminations  often  causes  a  number  of 
reflexes,  such  as  sneezing,  coughing,  increased  secretion  of  saliva,  and 
vomiting,  although  some  of  these  may  be  due  in  part  to  stimulation  of 
the  medullary  centres.  Evidence  of  the  stimulation  of  Other  Termi- 
nations is  presented  in  fibrillary  twitching  of  the  muscles  in  the  frog 
and  sometimes  in  mammals.  This  is  prevented  by  curara,  but  not  by 
section  of  the  nerves,  and  is  therefore  attributed  to  stimulation  of  the 
terminations  of  the  motor  nerves  in  muscles. 

Circulation. — ^The  effects  of  aconitine  on  the  circulation  have  given 
rise  to  some  misunderstanding  owing  to  their  complexity.  After  small 
quantities,  the  heart  does  not  seem  to  be  affected  in  man,  while  in 
maximal  therapeutic  amounts  it  is  very  often  accelerated  through 
the  nausea  induced  by  the  irritant  effect  in  the  stomach.  In  cases  of 
poisoning  the  heart  is  stated  to  be  very  slow  and  irregular,  and  this  can 
easily  be  elicited  in  anaesthetized  animals  by  the  injection  of  aconitine 
intravenously.  This  slowing  is  due  to  stimulation  of  the  inhibitory 
centre  in  the  medulla,  and  is  absent  in  experiments  in  which  the  vagus 
nerves  have  been  divided  previously  to  the  injection  or  in  which  atropine 
has  paralyzed  the  inhibitory  terminations  in  the  heart. 

In  large  doses  aconitine  exerts  a  further,  direct  action  on  the  heart, 
which  suddenly  accelerates  from  the  slow  vagus  rhythm  to  one  far 
above  the  normal.'  Soon  irregularities  follow  of  many  different  forms, 
one  of  the  most  common  being  reversal  of  the  beat,  in  which  the  ven- 
tricle contracts  before  the  auricle  and  gives  the  rhythm  to  the  heart. 
Other  arrhythmias  also  are  attributable  to  the  same  increase  in  the 
excitability  of  the  heart  muscle,  which  is  manifested  in  numerous 
extrasystoles  in  the  auricle  and  ventricle,  or  in  groups  of  rapid  rhythm 
arising  from  one  or  other  chamber  and  alternating  with  periods  of  fairly 
regular  rhythm.  The  conduction  power  of  the  heart  muscle  is  lessened 
and  this  leads  to  intermissions  of  the  ventricle  or  auricle.  And  changes 
occur  in  the  contractility,  so  that  pulsus  alternans  often  appears.  All 
of  these  effects  may  be  elicited  at  the  same  time,  giving  an  extremely 
complicated  tracing.  Finally  the  ventricle  passes  into  fibrillation  and 
the  circulation  ceases.  These  changes  arise  from  direct  action  on  the 
heart  muscle,  but  there  is  no  reason  to  suppose  that  it  is  affected  by 
therapeutic  doses.  After  section  or  paralysis  of  the  vagus,  a  much  larger 
(juantity  of  aconitine  is  required  to  produce  the  acceleration  and  final 
delirium  than  when  the  nerves  are  intact.  The  frog's  heart  is  affected 
by  aconitine  in  the  same  way  as  the  mammal's  and  presents  the  same 
diversity  in  rhythm. 

The  blood-pressure  in  mammals  falls  rapidly  from  the  lessened  out- 
put of  the  heart  in  the  stage  of  vagus  stimulation.  After  the  stage  of 
acceleration  has  set  in,  the  blood-pressure  becomes  extremely  irregular, 


428  SUBSTANCES  ACTING  AFTER  ABSORPTION 

alternately  sinking  to  zero  and  remaining  at  that  point  for  some 
seconds  and  again  attaining  a  fair  height.  The  vasomotor  centre  seems 
exentualiy  to  become  paralyzed,  while  the  vasomotor  nerves  and  their 
terminations  in  the  periphery  remain  unatl'eeted. 

The  Respiration  is  early  affected  in  aconitine  poisoning;  it  becomes 
much  slower,  the  movements  are  labored,  and  the  animal  suffers  from 
marked  dyspnoea.  In  fatal  cases  the  respiration  soon  becomes  inter- 
rupted by  convidsions,  and  in  the  intervals  between  these  becomes 
weaker  and  eventually  ceases.  The  action  appears  to  be  a  direct  one 
on  the  respiratory  centre,  which  is  paralyzed  before  the  heart  begins  to 
fibrillate  as  a  general  rule,  but  sometimes  continues  to  act  for  a  few 
seconds  later. 

Central  Nervous  System. — The  higher  centres  seem  to  be  almost  un- 
affected by  the  drug,  for  consciousness  has  often  remained  to  the  end, 
and  when  this  is  not  the  case,  the  mental  symptoms  are  to  be  ascribed 
to  the  changes  in  the  heart  and  respiration.  The  muscular  weakness 
and  depression  felt  after  small  quantities  appear  to  arise  from  the 
nausea  and  not  from  anj'  direct  nervous  action.  Some  of  the  lower 
centres  in  the  medulla  oblongata  are  directly  affected;  thus  the  cardiac 
inhibitory  centre  is  excited  by  large  doses  and,  according  to  some  authors, 
the  vasoconstrictor  centre  shares  in  the  stimulation,  but  this  is  not 
established  satisfactorily.  The  respiratory  centre  on  the  other  hand  is 
depressed  and  finally  paralyzed,  w'hile  the  rest  of  the  central  nervous 
system  is  shown  to  be  still  irritable  by  the  occurrence  of  convulsions. 

The  peripheral  nerve  trunks  are  paralyzed  by  the  ai:)plication  of 
aconitine  to  them  and  this  is  said  to  occur  in  the  frog  when  aconitine 
is  injected  hjq^odermically.  The  muscles  do  not  respond  to  aconitine 
except  in  much  higher  concentration. 

The  Secretion  of  saliva  is  greatly  increased  by  aconitine  from  the 
irritation  of  the  sensory  terminations  in  the  mouth  and  from  the 
nausea.  The  cold  perspiration  observed  in  poisoning  may  be  ascribed 
to  the  collapse  rather  than  to  any  direct  action  on  the  sweat  glands, 
although  Aubert  states  that  aconitine  is  a  powerful  diaphoretic  in 
itself. 

Aconitine  sometimes  reduces  the  Temperature  both  in  fe^•er  and  in 
normal  animals,  but  the  precise  way  in  which  this  action  is  elicited  is 
imknown.  Brunton  and  Cash  found  that  after  aconite  the  temjiera- 
ture  fell  more  rapidly  than  usual  if  the  animal  was  kept  in  a  cool  bath, 
but  rose  more  readily  if  it  was  subjected  to  external  warmth;  this 
observation  would  seem  to  indicate  that  aconite  renders  the  tempera- 
ture centres  less  sensitive. 

In  cases  of  Poisoning  in  animals,  atropine  has  been  found  to  alleviate 
the  symptoms  and  not  infrccjuently  to  lead  to  recovery  after  doses 
which  would  otherwise  have  been  fatal.  This  improvement  is  more 
especially  marked  in  the  respiration,  which  may  resume  its  normal 
character  and  persist  until  heart  paralysis  sets  in.  The  irregularity  of 
the  heart  and  the  final  delirium  cordis  are  also  retarded  \ery  consider- 
ably by  atr()i)inc,  and  it  is  i)()ssiblc  that  this  cardine  action  may  be  the 


ACONITINE  429 

explanation  of  the  improvement  of  the  r(>spiration,  which  is  strength- 
ened by  a  more  regular  supply  of  blood  to  the  centre.  Atropine  appears 
to  be  the  antidote  from  which  most  is  to  be  hoped  for  in  cases  of  aconite 
poisoning. 

Aconitine  is  Excreted  mainly  by  the  urine.  Minute  quantities  have 
also  been  found  in  the  saliva  and  bile. 

Benzaconine  is  very  much  less  poisonous  than  aconitine  and,  in  fact,  can 
scarcely  be  included  among  active  poisons,  though  very  large  quantities  act 
on  the  heart,  slowing  it  and  rendering  it  irregular,  and  also  depress  the  respira- 
tion. It  has  no  effect  on  the  sensory  terminations.  Aconine  itself  is  almost 
inactive,  but  large  quantities  strengthen  the  heart  beat  and  paralyze  the  termina- 
tions of  the  motor  nerves  like  curara.  It  seems  unlikely  that  these  alkaloids 
have  any  influence  on  the  action  of  the  aconite  preparations,  although  the 
possibility  cannot  be  excluded  at  present. 

The  alkaloids  obtained  from  some  other  species  of  Aconitum .  have  been 
found  to  differ  considerably  from  aconitine  and  pseudaconitine  in  their  action. 
In  Aconitum  septentrionale  three  bases  lappaconitine,  septeritrionaline,  and 
cynoctonine  have  been  discovered.  Lappaconitine  causes  clonic  convulsions, 
vomiting,  dyspnoea  and  finally  paralysis  of  the  respiration  and  heart,  and  in 
the  frog  lessens  the  sensibility  of  the  skin.  Septentrionaline  does  not  cause 
poisoning  when  taken  internally,  but  injected  subcutaneously  induces  local 
anaesthesia  and  later  paralysis  of  the  motor  terminations  like  curara.  Cynoc- 
tonine is  also  inactive  when  swallowed  and  is  less  poisonous  than  the  others 
when  applied  by  hypodermic  injection,  when  it  causes  tonic  and  clonic  convul- 
sions which  are  not  generally  followed  by  paralysis.  Two  alkaloids,  lycaconi- 
tine  and  myodonine,  have  been  found  in  Aconitum  lycoctonum,  and  induce 
almost  identical  symptpms.  They  increase  the  reflex  excitability,  and  this  is 
followed  by  convulsions  and  later  by  paralysis  of  the  terminations  of  the  motor 
nerves  and  by  failure  of  the  heart. 

Preparations. 

Aconitum  (U.  S.  P.),  Aconiti  Radix  (B.  P.),  the  root  of  Aconitum  Napellus, 
Monk's-hood,  containing  0.5  (0.4  B.  P.)  per  cent,  of  aconitine. 

TiNCTURA  Aconiti  (U.  S.  P.),  0.045  per  cent.;    dose,  0.6  c.c.  (8  mins.). 

TiNCTURA  Aconiti  (B.  P.),  0.04  per  cent.;  2-5  mins. 

Linimentum  Aconiti  (B.  P.),  0.2  per  cent. 

Aconitina  (U.  S.  P.,  B.  P.),  an  alkaloid  obtained  from  aconite  root.  Com- 
mercial aconitine  very  often  contains  large  amounts  of  aconine  and  benzaco- 
nine, and  therefore  varies  considerably  in  activity.    Dose,  0.15  mg.  (too  gr.). 

Ungventum  Aconitince  (B.  P.),  2  per  cent. 

Staphisagria  (U.  S.  P.),  Staphisagriae  Semina  (B.  P.),  the  dried  ripe  seeds 
of  Delphinium  staphisagria,  stavesacre. 

Therapeutic  Uses. — Aconite  is  employed  to  some  extent  to  slow  the 
pulse  and  reduce  the  temperature  in  fever.  Accurate  observations 
show  that  it  has  no  effect  in  slowing  the  pulse  when  given  in  thera- 
peutic doses,  and  its  action  on  the  temperature  is  very  uncertain.  It 
has,  therefore,  been  replaced  by  the  newer  and  more  powerful  group  of 
antipyretics  for  this  purpose. 

The  action  of  aconitine  on  the  sensory  ner\'e  terminations  suggested 
its  local  use  in  cases  of  neuralgia,  and  there  is  some  evidence  that  its 
application  relicNes  this  condition,  though  it  cannot  be  said  to  be  beyond 


430  SUBSTANCES   ACTING   AFTER   AliSORPTlON 

question.  Either  tlie  tineture,  or  a  2  per  eeiit.  solution  of  the  alkaloid 
in  oil,  or  the  ointment  of  the  B.  P.  may  be  employed  externally.  Aeoni- 
tine  has  also  been  injected  sulieutaneously  (yiro-nr  rng-)  i"  neuralgia, 
but  this  mode  of  ai)plication  is  not  to  be  recommended,  as  it  causes 
very  severe  pain,  which  in  some  cases  lasts  a  long  time.  Aconitine  is 
the  most  poisonous  of  the  alkaloids,  0.2  mg.  (;5,yo  gr.)  taken  by  the 
mouth  inducing  distinct  symptoms  in  man,  and  its  use  in  ointment  or 
solution  must  be  guarded.  The  internal  administration  of  aconite  in 
neuralgia  does  not  seem  to  be  followed  by  any  improvement.  Staves- 
acre  is  scarcely  used  in  medicine  at  present. 

Bibliography. 

Ringer  and  Murrell.     Journ.  of  Physiol.,  i,  p.  232. 

Boehm  u.  Warlmann,     Verhandl.  d.  phys.-med.  Gesellsch.  zu  Wiirzhurg,  1872,  p.  63. 

Cushny.     Heart,  vol.  i,  p.  1. 

Rosendahl.     Arb.  a.  d.  pharmak.  Instit.  Dorpat,  xi,  p.  1  (bibliography  up  to  1895). 

Cash  and  Dunstan.     Trans.  Royal  Society,  cxc.,  p.  239;    ccviii,  p.  39,  and  ccix,  p.  97. 

Schiller.     Arch.  f.  Anat.  u.  Phys.,  1904,  p.  248.     (Delphinine.) 

Hartung.     Arch.  f.  exp.  Path.  u.  Pharm.,  Ixvi,  pp.  1,  58;    Ixix,  p.  176. 

Price.     Proc.  Roy.  Soc.  of  Medicine,  Therapeut.  Section,  May  16,  1911. 


XXII.    VERATRINE. 

Several  species  of  the  genus  Veratrum  have  been  found  to  contain 
alkaloids,  the  most  important  of  which  resemble  each  other  in  many 
respects,  and  also  present  many  points  of  analogy  to  those  of  the  pre- 
ceding group. 

Vcrafrinc  is  a  mixture  of  two  isomeric  alkaloids  one  of  which  is  crys- 
talline (Ccvadinc),  the  other  amorphous  (Vcrafridiue),  which  occur  in 
Veratrum  Sabadilla  (Asagrtea  officinalis  or  Schaniocaulon  officinale), 
cevadilla,  and  perhaps  also  in  Veratrum  N'iride  and  V.  album,  Green 
and  AVhite  Hellebore.^  Protoreratrine  is  the  chief  acti\-e  principle 
of  both  these  species  of  Veratrum.  Alkaloids  of  this  series  have  been 
found  in  several  species  of  Zygadenus,  the  Death  Camas,  which  is  an 
im[)ortant  cattle  poison  in  the  Western  United  States. 

I'^acli  of  those  alkaloids  is  accoiupanicd  by  a  number  of  others,  most  of  wliieh 
arc  imperfectly  investigated  chemically  and  ])harmac()lugically.  In  cevadilla, 
in  addition  to  Veratrinc,  there  are  found  CcvadiUinc,  Sabailiiic,  Sdhadininc, 
and  Sahdtrinc.  In  white  hellel)ore,  Protovcratriiie  is  accompanied  by  Jcrvine, 
I'seudojervine,  Rvbijcrvine,  Protoreratridiiie,  and  otliers.  Green  hellebore  con- 
tains the  same  alkaloids  as  the  white  species,  but  in  smaller  quantity.  Jervine, 
Sal)adine,  and  Sabadinine  arc  known  to  possess  some  action  on  the  organism; 
Cevadilline  has  not  been  examined,  while  the  others  are  said  to  be  inactive. 

Veratrine  (CaJI^NOg)  and  i)rotoveratrine  (Cs-IIiiNOn)  are  both  powerful 
alkaloids,  the  latter  almost  rivaling  aconitine  in  its  toxicity.  Like  aconitine, 
each  of  these  may  be  decomposed  into  a  base  and  acid,  veratrine  forming 
angelic  acid  and  cevinc,  while  i)rotoveratrine  forms  isobutyric  acid  and  a  similar 
l)ase. 

'  Hcllfliore  is  also  the  pof)ii!ar  name  of  Helloborus  iiiRor,  which  differs  entirely  from 
Veratrum  in  its  principles  and  also  in  its  action. 


VERATRINE  431 

The  effects  of  veratrine  resemble  those  of  acoiiitiiie  very  closely  in 
their  general  character  and  particularly  in  regard  to  the  sensory  ter- 
minations; but  the  muscles  present  a  curious  reaction  to  veratrine, 
which  is  entirely  absent  in  aconitine  poisoning. 

Symptoms. — The  symptoms  in  man  and  other  mammals  commence 
with  prickling  and  burning  in  the  mouth  followed  by  a  sensation  of 
warmth  in  the  stomach,  marked  salivation,  nausea,  and  ^•omiting. 
The  bowel  is  more  invobed  in  the  effects  than  is  the  case  in  aconitine 
poisoning,  for  violent  purging  accompanied  by  severe  colic  is  a  com- 
mon symptom.  The  prickling  sensation  soon  spreads  from  the  mouth 
and  throat  to  the  skin,  and  is  generally  followed  by  profuse  perspira- 
tion. The  pulse  becomes  slow  and  irregular,  the  respirations  slow 
and  labored.  Fibrillary  contractions  of  the  muscles  and  convulsions 
are  generally  observed,  and  after  some  time  collapse  sets  in  and  is 
followed  by  unconsciousness  and  eventually  by  respiratory  failure. 

Action. — When  veratrine  is  applied  in  ointment  to  the  Skin  the 
same  prickling,  warm  sensation  may  be  elicited  locally,  and  some  of 
the  poison  is  absorbed,  as  is  shown  by  these  symptoms  sometimes 
occurring  in  other  parts  of  the  body.  The  cause  of  this  is,  as  in  the 
case  of  aconite,  stimulation  of  the  terminations  of  the  sensory  nerves. 
This  action  causes  violent  sneezing  and  coughing  when  small  quanti- 
ties of  veratrine  come  in  contract  with  the  sensitive  mucous  membranes 
of  the  nose  and  throat.  After  the  irritant  action  has  lasted  for  some 
time,  the  sensory  terminations  in  the  skin  become  less  sensitive,  and  a 
feeling  of  numbness  and  of  cold  is  noted.  Proto veratrine  seems  to 
cause  less  irritation  of  the  sensory  terminations  than  veratrine,  and  the 
subsequent  local  anaesthesia  is  more  complete. 

The  Nausea  and  Vomiting,  which  are  invariably  present  in  veratrine 
poisoning,  may  be  due  in  part  to  the  irritation  of  the  sensory  termi- 
nations of  the  stomach,  but  must  probably  be  attributed  for  the  chief 
part  to  central  action.  The  salivation  and  profuse  perspiration  may 
be  merely  secondary  to  this  emetic  effect,  or  the  poison  may  act  on  the 
glands  directly;  a  large  cutaneous  secretion  follows  its  injection  in  the 
frog.  Nothing  is  known  with  certainty  regarding  the  cause  of  the 
Purgation,  but  it  is  presumably  induced  by  some  action  on  the  nervous 
mechanism  of  the  intestine. 

The  most  characteristic  action  of  veratrine,  howe\-er,  is  that  on  the 
Striated  Muscles.  If  a  small  quantity  be  injected  into  the  lymph-sac 
of  a  frog  a  curious  clumsiness  and  awkwardness  in  the  movements 
becomes  apparent,  and  after  a  few^  minutes  it  is  evident  that  this  is 
due  to  inability  to  relax  its  muscles.  When  a  muscle  is  exposed,  it  is 
seen  to  contract  as  rapidly  as  usual,  but  instead  of  immediately  relax- 
ing again,  it  remains  shortened  and  offers  resistance  to  the  contraction 
of  the  opposing  muscles.  The  animal  can  no  longer  coordinate  its 
movements  therefore;  for  example,  it  can  no  longer  extend  a  limb 
immediately  after  flexing  it,  as  it  does  ordinarily  in  crawling,  and 
locomotion  becomes  very  slow  and  ungainly. 

This  characteristic  action  is  most  easily  seen  on  exposing  an  excised 


SUBSTANCES   ACTISd   AFTER   ABSORPTION 


frog's  muscle  to  a  solution  of  vcratrine;  as  long  as  the  muscle  remains 
at  rest  no  change  is  seen,  but  on  stimulating  it  with  a  single  induction 
shock,  it  is  found  that  the  height  of  the  contraction  is  increased  and  the 
second  part  of  the  cur\e  is  extraordinarily  prolonged  (Fig.  61).  Instead 
of  the  almost  instantaneous  return  to  the  base  line  seen  in  the  normal 
tracing,  the  cwvxe  shows  generally  a  slight  undulation,  and  then  a  very 
slow  fall,  the  period  of  relaxation  generally  being  20-30  times  as  long 
as  that  in  the  unpoisoned  muscle,  and  the  whole  contraction  lasting 
5-10  seconds  in  favorable  circumstances. 

Fig.  61 


a  b 

Tracings  of  muscular  contractions  from  the  gastrocnemius  of  the  frog,  a,  normal; 
b,  three  successive  contractions  taken  at  intervals  of  one  minute,  five  minutes  after  the 
injection  of  veratrine.  The  contraction  is  higher  and  much  more  prolonged  than  in  a, 
and  the  lever  returns  very  slowly  to  the  base  line. 


Cold  and  fatigue  and  high  temperature  antagonize  the  veratrine  at-tion, 
and  restore  the  normal  tracing;  on  the  other  hand,  vcratrine  removes  the 
fatigue  effect  in  the  muscle  curve.  During  the  prolonged  contraction,  more 
heat  is  formed  than  in  a  normal  contraction,  and  the  absolute  strength  of  the 
muscle  is  also  increased,  so  that  it  contracts  against  a  greater  weight  than  usual. 
Larger  doses  finally  paralyze  the  frog's  muscle,  the  form  of  tlie  tracing  first 
returning  to  the  normal  and  then  becoming  weaker  and  disappearing.  The 
irritability  of  the  muscle  is  not  increased  by  veratrine,  but  falls  in  the  later 
stages;  the  indirect  irritability  also  lessens  owing  to  weakness  and  final  jiaralysis 
of  the  nerve  ends.  These  muscular  phenomena  arc  best  seen  in  the  frog,  but 
can  also  be  elicited  in  warm-blooded  animals  by  very  large  doses;  they  are  not 
so  obvious  in  the  latter  because  the  quantity  necessary  to  induce  them  is  suffi- 
cient to  affect  the  respiratory  centre.  The  contraction  is  not  a  tetanus,  but 
a  prolonged  single  twitch,  as  is  shown  by  the  electrical  reaction.  The  muscle 
fibre  is  affected  directly  and  not  through  the  nerve-endings.  Protoveratrine 
has  less  tendency  to  prolong  the  muscle  contraction,  but  the  frog's  sartorius 
exposed  to  it  often  shows  the  typical  effect.  It  jxaralyzes  muscle  moi-c  readily 
than  veratrine,  but  has  less  effect  on  the  nerve  terminations. 

The  Nerve  fibres  are  paralyzed  by  veratrine  directly  applieil  to  them,  and 
also  by  protoveratrine  though  less  powerfully. 

Circulation.  — "^riie  ventricular  systole  of  the  frog's  heart  is  at  first 
stronger  and  more  prolonged,  and  soon  it  (lilat(>s  oidy  half  as  olten 
as  it  did   at    first,   wliilc   the   auricles   maintain   their  oriu'inal  rhythm. 


VERATRINE  433 

This  is  evidently  due  to  action  on  the  muscle;  the  contraction  is  so 
prolonged  as  to  limit  the  number  of  diastoles,  and  the  ventricle  can 
therefore  react  only  to  every  alternate  contraction  of  the  auricle. 
After  this  "half-rhythm"  has  persisted  for  some  time,  the  contrac- 
tions become  slower  and  weaker,  and  the  heart  finally  comes  to  a 
standstill. 

In  mammals  the  chief  circulatory  symptoms  arise  from  stimulation 
of  the  medullary  centres,  which  produces  slo^^•ing  of  the  heart  and  a 
decrease  in  its  output,  while  at  the  same  time  the  peripheral  vessels 
are  contracted  by  the  increased  activity  of  the  vasomotor  centre. 
After  large  quantities  the  terminations  of  the  vagus  are  paralyzed, 
and  the  vasomotor  centre  is  at  the  same  time  depressed,  so  that  the 
pulse  becomes  quicker,  but  the  blood-pressure  is  somewhat  lowered. 
In  the  mammalian  heart  no  such  prolongation  in  the  systole  is  seen 
as  in  the  frog's,  but  that  a  slight  stimulant  action  is  exercised  by  vera- 
trine  is  shown  by  the  fact  that  very  large  doses  quicken  the  rhythm 
even  after  atropine.  Veratrine,  therefore,  seems  to  resemble  aconitine 
in  its  efl'ects  on  the  mammalian  circulation,  but  much  larger  quantities 
are  required  to  produce  the  same  effects,  and  the  more  evident  symp- 
toms of  stimulation  of  the  myocardium  are  not  elicited. 

The  Respiratory  Changes  under  veratrine  also  resemble  those  under 
aconitine,  and  the  cause  of  death  is  paralysis  of  the  respiration. 

The  Central  Nervous  System  is  affected  in  the  same  way  as  under 
aconitine.  Some  of  the  medullary  centres  are  stimulated  at  first  and 
finally  depressed.  The  highest  centres  seem  less  affected  than  the 
spinal  cord  and  medulla  oblongata,  for  complete  consciousness  has 
remained  until  immediately  before  death  in  several  fatal  cases. 

The  Temperature  is  sometimes  reduced  by  veratrine,  but  is  stated 
to  be  higher  than  the  normal  in  some  instances.  In  cases  of  poisoning 
in  mammals  atropine  is  said  by  Lissauer  to  have  some  value,  probably 
owing  to  its  action  on  the  respiratory  centre  and  on  the  vagus  termina- 
tions in  the  heart. 

As  regards  the  other  alkaloids  of  this  series,  jervine,  sabadilline,  and  saba- 
dinine  seem  to  possess  the  same  action  as  veratrine,  but  are  much  less  poison- 
ous. Protoveratrine,  which  has  less  stimulant  effect  on  the  sensory  termina- 
tions and  on  the  muscle  fibres,  is  much  more  poisonous.  Its  action  resembles 
that  of  aconitine  as  much  as  that  of  veratrine,  and  it  may  therefore  be  regarded 
as  a  link  connecting  the  two  groups. 

Preparations. 

Veratrina  (U.  S.  P.),  a  mixture  of  alkaloids  obtained  from  the  seeds  of 
Asagrsea  officinalis,  insoluble  in  water  but  soluble  in  alcohol.    Dose,  2  mg. 

(3^0  gr.). 

Oleatum  VeratrincB  (U.  S.  P.),  2  per  cent. 

Therapeutic  Uses. — Veratrine  is  used  in  the  form  of  the  oleate  or 
ointment  as  an  external  application  in  cases  of  neuralgia  and  is  certainly 
a  safer  remedy  than  aconite.  Neither  its  pharmacological  action  nor 
therapeutic  experience  supplies  any  indications  for  its  internal  use. 

28 


4;U  SUBSTANCES  ACTING  AFTER  ABSORPTION 

Hibli()(;r.vi'1IY. 

Bezold  u.  Hirt.     Uiitersuch.  aus  dem  phys.  Laboral.  zu  Wiirzburg,  i,  p.  75. 

Lissaucr.     Arch.  f.  cxp.  Path.  ii.  Pharin.,  xxiii,  p.  3G. 

Brunton  and  Cash.     Journ.  of  Physiol.,  iv,  p.  1. 

Overend.     Arch.  f.  exp.  Path.  ii.  Pharm.,  xxvi,  p.  1. 

Eden.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxix,  p.  440.     (Protovcratrine.) 

Schenk.     Pfliiger's  Archiv,  Ixi,  p.  494. 

Santesson.     Skand.  Arch.,  f.  Phys.,  xiv,  pp.  1,  4.30. 

Garten.     Pfliiger's  Arch.,  Ixxvii,  p.  485. 

Botazzi.     Arch.  f.  (Anat.  u.)  Phys.,  1901,  p.  377. 

Bucfianan.     Journ.  of  Physiol.,  xxv,  p.  137. 

Boehm.     Arch.  f.  exp.  Path.  u.  Pharm.,  Ixxi,  p.  2G9. 

XXm.     APOMORPHINE. 

When  morphine  is  acted  on  by  acids  and  by  some  other  dehydrating 
agents,  it  loses  a  molecule  of  water,  and  a  new  alkaloid  is  formed, 
Apomoryhine  (C17H17NO2) . 

Through  this  change  the  action  of  the  original  alkaloid  is  consid- 
erably modified;  apomorphine  preserves  the  stimulant,  but  loses  to  a 
great  degree  the  depressant  action  of  morphine  on  the  central  nervous 
system.  This  stimulant  action  extends  over  the  whole  central  nervous 
system  in  animals,  but  is  most  developed  in  the  "vomiting  centre"  of 
the  medulla  oblongata. 

Symptoms. — In  man  apomorphine  in  doses  of  5-10  mg.  (yV-^  gr.) 
induces  within  ten  to  fifteen  minutes  nausea  and  vomiting,  accompanied 
by  the  usual  attendant  phenomena,  but  with  no  symptoms  which  cannot 
be  directly  included  in  these.  Very  often  the  nausea  passes  off  imme- 
diately after  the  evacuation  of  the  stomach,  but  when  larger  quantities 
have  been  administered,  repeated  vomiting  and  retching  may  occur. 
Occasionally  depression  and  sleep  follow  the  emesis  after  even  small 
doses. 

The  attendant  symptoms  are  profuse  salivation,  increased  secretion 
of  the  mucous  glands  of  the  nose,  throat  and  bronchial  passages,  tears, 
and  a  cold  perspiration.  A  feeling  of  depression  and  muscular  weakness 
and  acceleration  of  the  pulse  are  also  well-known  symptoms  accompany- 
ing nausea  and  vomiting,  and  are  present  after  apomorj)hine.  These 
are  all  to  be  regarded  as  sequela?  of  the  emetic  action,  however,  and  not 
as  due  to  the  direct  action  of  the  drug  on  the  glands  and  other  organs. 
In  a  few  instances  the  depression  and  weakness  have  passed  into  alarm- 
ing collapse,  but  no  actual  fatality  is  recorded  from  the  use  of  apo- 
niorj)hin(\ 

N'cry  small  doses  of  ai)onu)rj)liine  may  induce  the  secondary  symj)- 
toms  without  actual  vomiting.  Thus  the  saliva,  perspiration,  tears 
and  other  secretions  may  be  augmented  by  quantities  which  are  too 
small  to  act  as  emetics,  though  tliere  is  no  question  that  these  are  due 
to  the  coninienciiig  emetic  iiction. 

Ap()ni()r])hine  induces  \'oniiting  throngii  changes  in  the  medulhi 
oblongata  and  not  by  irritation  of  the  stomach.  This  is  shown  by  the 
fact  that  it  acts  nnich  more  quickly  and  in  smaller  doses  when  it  is 


APOMORPHINE  435 

injected  liypodermieally  or  iiitramuscularly  than  when  it  is  swallowed, 
and  also  by  the  fact  that  if  the  medulla  be  brushed  with  apomorphine 
solution,  \-omiting  follows  immediatel,y.  The  movements  of  vomiting 
may  also  be  induced  in  animals  after  the  removal  of  the  stomach  and 
intestine,  showing  that  the  condition  and  the  movements  of  the  stomach 
play  an  unimportant  part  in  the  evacuation  of  its  contents  by  apo- 
morphine. All  the  phenomena  in  man,  including  the  bronchial  secretion, 
the  perspiration  and  other  attendant  symptoms,  are  to  be  ascribed 
to  medullary  action. 

In  dogs  and  cats,  small  cpantities  elicit  the  same  effects  as  in  man, 
but  larger  doses  are  followed  by  symptoms  of  general  nervous  stimu- 
lation. In  the  herbivora,  which  are  incapable  of  vomiting,  these 
symptoms  follow^  the  injection  of  comparatively^  small  quantities  and 
are  much  more  marked.  The  rabbit,  for  example,  becomes  restless 
and  easily  alarmed;  it  moves  about,  climbs  up  the  walls  of  its  cage 
and  gnaws  anything  it  can  reach.  Circus  movements  are  developed 
very  often,  especially  in  the  dog,  the  animal  running  unceasingly  in  a 
circle  and  striking  against  obstacles  in  its  path,  apparently  uncon- 
scious of  all  its  surroundings  and  overcome  by  the  impulse  to  continual 
movement.  The  respiration  is  very  much  accelerated.  After  very 
large  quantities  the  movements  become  less  coordinated,  and  eventually 
tetanic  convulsions  set  in,  during  which  the  respiration  ceases,  while 
the  heart  continues  to  beat  for  some  time  afterwards. 

Apomorphine  is  said  to  have  some  anaesthetic  effects  on  the  cornea  when  a 
sohition  is  dropped  upon  it.  It  causes  cloudiness  and  consequent  dimness 
of  sight,  however,  and  has  not  been  used  practically  for  this  purpose.  Apo- 
morphine is  not  excreted  into  the  stomach  like  morphine,  nor  has  it  been  found 
in  the  mucous  membranes  of  the  air  passages,  and  it  is  possible  that  it  is  all 
decomposed  in  the  tissues.    No  tolerance  is  acquired  for  it. 

The  symptoms  induced  b}^  apomorphine  resemble  in  some  degree  those 
following  morphine  in  many  animals,  for  here  too  the  first  symptom  is  vomiting 
accompanied  by  signs  of  excitement,  which  are,  however,  generally  attended 
Ijy  those  of  depression  of  some  part  of  the  central  nervous  sj^stem.  In  man. 
however,  the  effects  are  very  different,  for  apomorphine  seems  to  have  lost  all 
the  depressant  action  of  the  parent  body,  although  here  again  it  must  be  re- 
membered that  morphine  occasionally  causes  vomiting,  so  that  apomorphine 
does  not  depart  so  far  from  the  type  of  the  opium  alkaloids  as  would  at  first 
appear. 

In  the  frog,  apomorphine  causes  a  transient  stimulation  of  the  central  nervous 
system,  followed  by  depression  and  paralj^sis. 

Apocodeitie  is  formed  from  codeine  in  the  same  way  as  apomorphine  from 
morphine,  but  it  differs  entirely  from  apomorphine  in  its  action  and  resembles 
nicotine  in  paralyzing  the  sympathetic  ganglia.  It  causes  purgation  when 
injected  hypodermically,  apparently  from  removing  the  normal  inhibition 
of  the  bowel  movements  (Dixon).  If  codeine  is  heated  with  hj-drochloric  acid, 
apomorphine  is  formed,  and  not  apocodeine. 

Preparations. 

Apomorphine  Hydrochloridum  (U.  S.  P.),  expectorant  0.002  G.  (Jf  gr.), 
emetic  0.05  G.  (to  gr.);  (B.  P.),  iWo  gr.  hypodermically,  To-i  gr.  by  the 
mouth. 


436  SUBSTANCES  ACTING  AFTER  ABSORPTION 

Injectio  ApomorphiNjE  Hypodermica  (B.  p.),  1  per  cent.,  5-10  inins. 

Aponiorphiue  hydrochloride  is  a  grayish-white  crj'stalUne  substance,  very 
s()hil)le  in  water  and  turning  dark  green  or  even  black,  especially  when  kept 
long  in  solution.  This  change  in  color  does  not  appear  to  impair  its  activity 
appreciably. 

Therapeutic  Uses. — Apomorphine  is  used  chiefly  as  an  emetic,  and 
for  some  purposes  presents  several  advantages  over  the  older  drugs 
employed  with  tliis  object,  inasmuch  as  it  acts  more  promptly  and  can 
be  administered  by  the  hypodermic  needle,  while  the  other  emetics 
cause  vomiting  by  irritating  the  stomach  and  have  to  be  given  by  the 
mouth,  which  is  a  serious  drawback  in  cases  of  poisoning.  The  more 
important  of  these  older  drugs  are  ipecacuanha,  tartar  emetic  (antimony), 
ammonium  carbonate,  the  sulphates  of  copper,  zinc  and  alum. 

Vomiting  is  not  now  such  an  important  method  of  treatment  as  it 
was  formerly,  and  the  emetics  are  less  frequently  employed  to  evacuate 
the  stomach  than  other  less  heroic  measures,  such  as  the  passage  of 
the  stomach  tube.  Emesis  may  be  indicated  in  poisoning,  and  here 
apomorphine  is  especially  useful.  But  in  the  great  majority  of  cases 
a  better  method  of  treatment  is  repeated  washing  of  the  stomach  by 
means  of  the  stomach  tube,  for  in  narcotic  poisoning  apomorphine  not 
infrequently  fails  to  act,  owing  to  the  depression  of  the  vomiting 
centre,  and  in  corrosive  poisoning  a  certain  amount  of  danger  attends 
its  use,  as  the  pressure  on  the  walls  of  the  stomach  exerted  by  the  con- 
traction of  the  diaphragm  and  abdominal  muscles  may  lead  to  the 
rupture  of  the  weakened  walls  of  the  organ.  In  irritant  poisoning, 
on  the  other  hand,  the  reflex  vomiting  set  up  is  generally  sufficient  to 
empty  the  stomach,  and  the  indications  are  rather  to  allay  the  gastric 
irritation  than  to  increase  it  by  causing  violent  movements  of  the 
abdominal  walls  by  apomorphine.  Emetics,  such  as  apomorphine, 
have  been  used  occasionally  to  cause  pressure  on  other  abdominal 
organs,  e.  g.,  on  the  gall-bladder  in  order  to  dislodge  a  calculus  or  plug 
of  mucus  in  the  ductus  choledochus,  but  this  treatment  is  not  to  be 
advised,  owing  to  the  risk  of  rupture  of  the  gall-bladder.  Occasionally 
emetics  are  used,  especially  in  children  to  expel  bodies  from  the  air 
passages,  as  violent  movements  of  expiration  are  produced  during 
emesis.  Apomorphine  is  comparatively  rarely  used  for  this  purpose, 
however.  In  cases  of  choking  due  to  foreign  bodies  lying  in  the 
pharynx,  vomiting  is  often  beneficial,  but  the  emetics  act  too  slowly 
to  be  of  benefit  here. 

A  second  use  of  emetics  is  in  inflammatory  conditions  of  the  respi- 
ratory passages;  the  object  here  is  to  induce  an  increased  secretion 
without  producing  emesis,  and  very  small  quantities  are  therefore 
used.  The  special  condition  in  which  this  class  of  remedies  is  of  ser- 
vice is  bronchial  irritation  with  a  sticky  mucous  secretion  which  causes 
cough,  but  can  only  be  expectorated  with  difliculty.  Tiie  indications 
are  for  a  mild  and  prolonged  action  such  as  can  be  induced  by  small 
doses  of  ipecacuanha,  antimony  and  similar  bodies,  rather  than  for  the 
more  transient  efl'ect  of  apomor])hinc,  but  the  latter  has  been  advised 
by  some  authorities. 


EMETINE  437 


Bibliography. 

Siebcrt.     Inaug.  Diss.,  Dorpat,  1871.    Archiv.  f.  Heilkunde,  xii.  p.  522. 

Quehl.     Inaug.  Diss.,  Halle,  1872. 

Harnack.     Arch.  f.  exp.  Path.  u.  Pharm.,  ii;  p.  254;   iii.  p.  64;    Ixi,  p.  343. 

Thumas.     Virchow's  Archiv,  cxxiii,  p.  44. 

Eggleston  and  Hatcher.     Journ.  of  Pharmacology,  iii,  p.  551. 

Dixon.     Jour,  of  Phys.,  xxx,  p.  97.    (Apocodeine.) 

XXIV.    EMETINE   (IPECACUANHA). 

Ipecacuanha  (Cephjelis  Ipecacuanha)  has  long  been  used  for  its 
emetic  and  expectorant  virtues,  and  until  recently  was  believed  to 
contain  only  one  alkaloid,  Emetine.  Paul  and  Cownley  have  shown, 
however,  that  this  so-called  principle  is  really  made  up  of  three  distinct 
alkaloids,  CeijhoBline  (C14H19NO2),  Emetine  (Ci4Hi«(CH3)N02),  and 
Psijchotrine;  emetine  is  methyl-cephseline,  and  cephseline  is  obtained 
from  psychotrine  by  reduction;  they  are  all  three  derivatives  of  iso- 
quinolinc,  and  emetine  and  cepha?line  resemble  each  other  in  their  action, 
while  psychotrine  is  said  to  be  almost  inert. 

Symptoms  and  Action. — When  administered  internally  emetine  has 
a  bitter,  acrid  taste,  and  produces  a  copious  salivary  secretion,  fol- 
lowed later  by  nausea  and  vomiting.  The  drug  is  generaly  largely 
eliminated  by  vomiting,  so  that  no  further  effects  are  obser^'ed. 

The  nausea  and  vomiting  are  accompanied  by  the  usual  symptoms 
— muscular  weakness  and  depression,  increased  secretion  of  saliva  and 
of  mucus  by  the  glands  of  the  throat  and  respiratory  passages,  often 
perspiration  and  generally  temporary  acceleration  of  the  pulse. 

Quantities  which  are  too  small  to  provoke  vomiting,  induce  pro- 
longed nausea  with  increased  mucous  secretion  along  the  respiratory 
passages  and  some  perspiration. 

Emetine  possesses  a  powerful  Irritant  Local  Action,  which  is,  how- 
ever, much  more  marked  in  certain  individuals  than  in  others.  The 
smallest  quantity  of  the  powdered  root  of  ipecacuanha  is  sufficient 
to  induce  in  the  subjects  of  this  idiosyncrasy  considerable  swelling 
and  injection  of  the  conjunctival  and  nasal  mucous  membranes,  Avith 
salivation,  tears,  sneezing,  coughing,  and  bronchial  catarrh.  ^  When 
applied  to  the  skin  as  a  liniment,  it  produces  redness,  itching  and 
occasionally  a  pustular  eruption,  but  when  injected  hypodermically 
the  alkaloids  do  not  irritate  the  subcutaneous  tissues. 

The  emetic  action  is  undoubtedly  due  to  ipecacuanha  irritating 
the  stomach,  and  is  thus  a  further  example  of  its  specific  action  on  the 
mucous  membranes.  Attempts  have  been  made  to  show  that  the 
vomiting  arises  from  stimulation  of  the  medullary  centre,  but  these 
have  not  been  convincing.  If  the  action  were  due  to  the  eftects  of  the 
drug  after  absorption,  vomiting  would  be  caused  by  a  smaller  dose 
injected  hypodermically  or  intravenously  than  is  necessary  by  the 
mouth;  but  it  is  found  that  a  dose  of  emetine  sufficient  to  cause  vomiting 
when  swallowed,  may  be  injected  without  any  effects  whatever.    In  the 


438  SUBSTANCES  ACTING  AFTER  ABSORPTION 

case  c)t"  a])(tiii()ri)Iiiiu',  oil  tlii'  other  luiiul,  in  which  the  action  is  central, 
the  hypochTniic  emetic  tlose  is  very  much  smaller  than  that  necessar\' 
when  it  is  ti;i\'en  by  the  mouth.  The  increased  bronchial  secretion, 
the  perspiration,  the  acceleration  of  the  pulse  and  other  attendant 
symptoms  are  similarly  reflex  in  origin  from  the  gastric  irritation  and 
do  not  indicate  any  direct  action  on  the  bronchi  and  other  organs. 

When  large  doses  are  injected  hypodermically,  emetine  induces  nausea, 
vomiting,  and  purging,  and  blood  is  frequently  voided  in  the  stools,  a  condi- 
tion of  collapse  follows,  and  the  animal  generally  dies  of  exhaustion  in  the 
course  of  a  few  hours  after  the  onset  of  the  symptoms.  Very  large  quantities 
injected  subcutaneously  or  intravenously  may  fail  to  elicit  vomiting,  but  the 
collapse  symi)toms  appear,  and  after  some  weak  con\'ulsive  movcnients,  the 
animal  dies  of  cardiac  failure.  In  those  cases  in  which  death  follows  rapidly 
on  tlie  injection,  no  pathological  lesions  may  be  found  after  death,  but  in  experi- 
ments where  smaller  quantities  are  injected,  and  the  animal  survivies  for  eighteen 
to  twenty-four  hours,  the  stomach  and  intestine  often  exhibit  the  appearances  of 
acute  gastro-enteritis.  The  nmcous  membrane  is  swollen,  congested,  and 
often  covered  with  a  muco-purulent  secretion  or  studded  with  ecchymoses,  and 
in  dogs  ulceration  is  often  present.  A  lesion  which  is  not  by  any  means  constant, 
l;)ut  which  occurs  in  a  considerable  number  of  animals  and  especially  in  rabl)its, 
is  fjedema  of  the  lungs. 

The  gastric  and  intestinal  symptoms  which  follow  from  these  large  hypo- 
dermic doses  suggest  that  emetine  is  excreted  by  the  mucous  membranes  of  the 
alimentary  canal,  and  that  it  induces  irritation  and  inflammation  in  the  course 
of  its  excretion.  In  man,  vomiting  has  followed  the  hypodermic  injection  of 
four  grains  of  emetine,  but  one  grain  administered  in  this  way  has  no  such 
effect. 

Emetine  injected  into  a  vein  weakens  the  heart's  action,  and  induces  a  fall 
of  blood-pressure,  but  when  it  is  injected  subcutaneously  or  given  by  the  mouth, 
the  heart  is  not  affected  directly. 

In  the  frog  emetine  does  not  cause  vomiting,  but  a  slowly  advancing  central 
paralysis  follows  its  injection,  the  spontaneous  movements  ceasing  early,  and 
later  the  reflex  excitability  disappearing.  The  contractions  of  the  heart  are 
rendered  weak  and  irregular,  and  eventually  cease  from  paralysis  of  the  cardiac 
nuiscle. 

Ipecacuanha  has  long  enjoyed  a  reputation  in  one  form  of  tropical 
dysentery,  and  the  discovery  that  the  cause  of  this  form  of  dysentery 
was  an  amoeba  (Entamoeba)  was  soon  followed  by  Roger's  demon- 
stration that  emetine  has  a  specifically  poisonous  action  on  this  i)arasite. 
This  specific  toxicity  extends  in  smaller  degree  to  ordinary  forms  of 
amoeba  also,  but  emetine  is  not  especially  destructive  to  some  other 
forms  of  i)roto'/oa.  This  destructive  action  is  exerted  on  entamcrba 
when  the  intestine  and  liver  are  infected  by  it.  The  quantity  of  emetine 
that  comes  in  contact  with  the  parasite  must  be  even  snudler  than 
that  of  quinine  in  cases  of  malaria,  and  it  is  quite  devoid  of  action  on 
the  tissues  in  which  the  parasite  is  embedded.  It  seems  probable  that 
the  emetine  reaches  the  an)(id)a^  in  the  stools  in  the  course  of  its 
excretion  by  the  intestinal  walls. 

Emetine  and  ceplueline,  the  two  chief  alkaloids  of  ipecacuanha,  re- 
send^le  each  other  closely  in  their  cfTects,  ceplueline  being  somewhat 
more  irritant  than  emetine.  Ipecacuanha  owes  its  action  to  the  alkaloids, 
and  dillVrs  from  them  only   in  acting  more  slowly  and  in   having  less 


EMETINE  4:50 

temlciicy  to  cause  purging  owing  to  its  containing  a  large  amount  of 
tannin.  The  relative  amoebicidal  action  of  the  two  alkaloids  has  not 
been  accurately  determined,  but  emetine  is  believed  to  be  sui)erior  to 
eephffiline. 

Preparations. 

U.  S.  P. — Ipecacuanha,  the  root  of  Cephsplis  Ipecacuanha  or  of  C.  acuminata, 
contains  at  least  2  per  cent,  of  alkaloids.  The  powdered  root  is  prescribed  in 
dysentery  in  ciuantities  of  2-4  G.  (30-60  grs.);  emetic,  1  G.  (15  grs.);  expecto- 
rant, 0.065  G.  (1  gr.). 

Fliddextradum  Ipecacuanhce,  (1.75  per  cent,  of  alkaloids)  expectorant,  0.05 
c.c.  (1  min.);  emetic,  1  c.c.  (15  mins.). 

Syrupus  Ipecacuanha,  (about  0.12  per  cent,  of  alkaloids)  expectorant, 
1  c.c.  (15  mins.);    emetic,  15  c.c.  (4  fl.  drs.). 

PuLVis  IPECACUANHiE  ET  Opii  (10  per  Cent,  each  of  ipecacuaidia  and  opium), 
Dover's  Powder,  0.5  G.  (S  grs.). 

B.  P. — Ipecacuanhse  Radix,  the  dried  root  of  Psychotria  Ipecacuanha, 
(2  per  cent,  of  alkaloids)  expectorant,  ^-2  grs.;  emetic,  15-30  grs.;  in  dysentery, 
30-60  grs. 

Extradum  Ipecacuanhce  Liquidum  (2  per  cent,  alkaloids),  |-2  mins. 

ViNUM  Ipecacuanhce,  expectorant,  10-30  mins;   emetic,  4-6  fl.  drs. 

PuLvis  Ipecacuanha  Compositus,  Dover's  Powder,  10  per  cent,  each  of 
ipecacuanha  and  opium,  5-15  grs. 

Piiuln  Ipecacuanhw  cum.  Scilla,  4-8  grs.  This  pill  is  formed  from  Dover's 
Powder,  and  contains  about  5  per  cent,  of  opium. 

Not  official. — Emetine  Hydrochloride.    Dose,  hypodermically  ^-1  gr. 

Therapeutic  Uses. — Ipecacuanha  has  been  largely  employed  as  an 
emetic,  and  although  it  has  been  replaced  for  some  purposes,  notably 
in  cases  of  poisoning,  by  apomorphine,  it  still  has  a  certain  field  of 
usefulness  in  cases  in  w^hich  an  emetic  is  indicated,  but  in  which 
the  hypodermic  method  is  objectionable,  as  in  children.  At  present 
ipecacuanha  is  used  chiefly  as  an  expectorant  in  the  treatment  of 
inflammatory  conditions  of  the  respiratory  passages.  For  this  pur- 
pose it  is  prescribed  in  very  much  smaller  quantities  than  those  neces- 
sary to  produce  emesis.  It  acts  indirectly  through  its  nauseating  prop- 
erties, and  has  the  advantage  that  its  action  is  much  more  prolonged 
than  that  of  apomorphine,  and  at  the  same  time  is  not  so  unpleasant 
as  that  of  several  metallic  substances,  such  as  tartar  emetic,  which  are 
used  for  the  same  purpose.  It  increases  the  secretion  of  the  bronchial 
mucous  membrane,  and  further  tends  to  render  it  more  fluid,  so  that 
the  mucus  can  be  coughed  up  more  easily.  The  increased  secretion 
may  also  be  of  service  by  protecting  the  inflamed  and  irritable  mem- 
brane from  the  cold  air  and  thereby  lessening  the  cough;  opium  is 
often  added  in  order  to  further  allay  coughing  by  depressing  the 
centre,  the  well-known  Dover's  powder  being  a  favorite  prescription 
for  this  purpose.  When  the  secretion  of  the  bronchi  is  already  exces- 
sive, and  the  cough  is  rather  to  be  encouraged  than  repressed,  these 
preparations  are  of  course  contra-indicated. 

Ipecacuanha  is  also  employed  as  a  diaphoretic,  either  alone  or  more 
commonly  as  Dover's  powder.  The  perspiration  is  not  so  copious  as 
that  following  pilocarpine  and  other  diaphoretics,  but  resembles  rather 


440  SUBSTANCES  ACT  IXC  AFTER  ABSORPTION 

that  produced  by  warmth  applied  to  the  skin.  Dover's  powder  is 
therefore  a  common  remedy  in  chills  and  in  commencins;  catarrh  of  the 
resi)iratory  passages. 

Ipecacuanha  is  used  very  largely  in  amoebic  dysentery,  in  which  it 
acts  as  a  specific.  Very  large  quantities  of  the  powdered  root  are  gen- 
erally required.  Many  prescribe  enough  to  cause  vomiting  at  first,  and 
then  follow  this  up  with  smaller  quantities  which  are  used  along  with 
morphine  or  ice,or  with  sinapisms  to  lessen  the  nausea  and  vomiting. 
Others  gi^'e  a  few  drops  of  laudanum  at  once,  and  when  the  medul- 
lary irritability  is  thus  reduced  and  there  is  less  danger  of  vomiting, 
prescribe  30-GO  grs.  (2-4  G.)  of  the  powdered  root,  and  continue  the 
treatment  ^^•ith  smaller  doses.  Another  method  consists  in  giving  the 
i])ecacuanha  enclosed  in  keratin  or  in  salol,  which  prevent  it  acting 
on  the  stomach,  but  are  dissolved  in  the  duodenum  and  thus  free  the 
ipecacuanha  in  the  intestine. 

But  all  these  cumbrous  methods  have  been  rendered  obsolete  by 
Roger's  discovery  of  the  brilliant  effects  of  the  alkaloid  emetine  when 
gi^•en  hypodermically  in  amoebic  dysentery  and  in  its  sequelae,  hepatitis 
and  hepatic  'abscess.  After  the  hypodermic  injection  of  1-2  grs.  in 
divided  doses  of  |-f  grs.  each,  the  amoebte  disappear  from  the  stools 
and  from  the  li\'er  in  a  large  proportion  of  cases,  and  an  immediate 
impro^'ement  in  the  symptoms  follows.  The  injection  is  unattended  by 
pain,  irritation  or  any  other  symptom;  the  soluble  hydrochloride  is 
dissolved  in  the  ordinary  way.  In  amoebic  liver  abscess,  Rogers  removes 
the  ])us  by  aspiration  and  then  injects  into  the  cavity  a  grain  of  emetine 
dissolved  in  1-2  oz.  of  sterile  saline  solution  to  destroy  the  ama'ba\ 
The  action  of  emetine  in  these  amebic  diseases  can  only  be  compared 
with  that  of  quinine  in  malaria;  and,  as  in  the  case  of  quinine,  it 
destroys  only  the  free  protozoa,  while  encysted  forms  escape,  and  may 
gi\'e  rise  to  relapses.  Emetine  is  valueless  in  dysentery  from  bacillary 
infection  and  other  intestinal  disorders. 

Ipecacuanha  has  been  recommended  in  very  small  quantities  as  a 

stomachic,  even  in  cases  of  vomiting,  and  its  action  on  the  mucous 

'membrane  might  be  expected  to  be  of  value  in  some  cases;  but  it 

very  often  fails  to  have  any  effect,  and  is  not  widely  used  for  this 

purjiose. 

BlBLIOGRAPIlV. 

Djjce  Duckworth.     St.  Bartholomew  Hospital  Reports,  v,  p.  21S;    vii,  p.  91. 

Podwyasolzki.     Arch.  f.  cxp.  Path.  u.  Pharm.,  xi,  p.  231. 

Lowin,  Kimura,  and  Zepf.     Arch,  internat.  de  Pharniacodyii.,  xi,  pp.  9,  AO't;    xii,  p.  Mr>. 

Wild.     Lancet,  189.''.,  ii,  p.  1274. 

Henderson  and  Taylor.     Journ.  of  Pliarnia(rolofj;y,  ii,  p.  15.'i. 

Rogers.     Dysenteries;    their  differentiation  and  treatment,  London,  lOl.'i. 

Vedder.     ,Jonr.  AmiT.  Med.  Assoc,  1914,  i,  p.  501. 

XXV.      COLCHICINE. 

Colchicine  and  roh-hkeine  are  two  nearly  related  bodies  found  in  the 
seeds  nnd  conn  of  ('olchienni  autiMnii;ile,  which  owes  its   activity   to 


COLCHICINE  441 

their  presence.  Colchicine,  (CH30)3CioH3(C6H60).OCH3.NHCOCH3,  is 
the  methyl  ester  of  colchicine,  which  is  much  less  active  pharmaco- 
logically/ Colchicine  is  feebly  basic,  while  colchiceine  is  slightly  acid 
in  reaction. 

Symptoms.— No  symptoms  whatever  follow  the  use  of  colchicuni  in 
small  quantities.  Large  doses,  corresponding  to  4-5  mgs.  of  colchicine, 
cause  diarrha?a  with  some  griping  in  susceptible  persons,  and  in  the 
therapeutic  use  of  the  drug  purging  is  often  observed ;  symptoms  only 
arise  several  hours  after  the  drug  is  administered,  and  this  interval  is 
not  shortened  by  increasing  the  dose. 

In  poisoning  with  colchicine,  whether  given  by  the  mouth  or  injected 
hypodermically,  the  s^onptoms  arise  from  the  alimentary  tract.  Pain 
in  the  gastric  region  is  followed  by  salivation,  nausea,  vomiting,  and 
diarrhoea.  At  first  the  evacuations  are  the  ordinary  contents  of  the 
stomach  and  intestine,  but  afterward  a  quantity  of  sticky  mucous 
fluid  may  be  ejected,  often  streaked  with  blood.  Later,  a  condition 
of  depression,  apathy  and  collapse  follows,  and  the  movements  become 
slow  and  difficult,  more  especially  in  the  posterior  extremities,  which 
eventually  become  completely  motionless;  the  paralysis  then  progresses 
upward  until  the  movements  of  the  fore  limbs  and  respiratory  muscles 
are  involved,  when  death  occurs  from  asphj-xia.  In  man  the  intelligence 
remains  until  death,  though  there  is  generally  some  giddiness  and 
precordial  anxiety  and  occasionally  some  confusion  or  even  delirium 
preceding  the  collapse. 

In  mammals  poisoned  with  colchicine  the  alimentary  canal  exhibits  all 
the  appearances  of  acute  gastro-enteritis,  with  numerous  ecchymoses, 
especially  in  the  upper  part  of  the  bowel.  In  less  acute  cases  these 
inflammatory  symptoms  are  less  marked,  and  in  man  there  is  seldom 
more  than  catarrh  of  the  duodenum. 

The  Circulation  is  but  little  affected  apparently.  In  animals,  the 
blood-pressure  and  heart  rhythm  remain  normal,  and  though  a  small, 
rapid  pulse  may  be  one  of  the  features  of  the  poisoning  in  man,  this 
is  due  to  the  collapse  rather  than  to  any  direct  action  on  the  circu- 
latory organs. 

The  Respiration  is  slow,  but  is  deep  and  full  at  first.  Later  it  becomes 
shallow,  and  the  failure  of  the  centre  is  the  cause  of  death,  the  heart 
continuing  to  beat  for  some  time  afterward. 

The  Movements  of  the  Bowel  are  much  hastened  when  the  symptoms 
set  in,  and  Dixon  states  that  colchicine  acts  on  the  bowel  in  the  same 
way  as  pilocarpine,  and  that  its  action  is  antagonized  by  atropine; 
l)ut  this  is  entirely  inadequate  to  explain  the  acute  inflammatory 
appearances,  which  are  evidently  due  to  an  irritant  action  on  the 
mucous  membrane.  Increased  movement  is  said  to  be  induced  in 
the  plain  muscle  of  the  spleen,  uterus,  and  bronchial  muscle  from  a 
pilocarpine-like  action. 

When  Locally  Applied  to  sensitive  mucous  membranes,  or  when 
injected  hypodermically,  colchicine  is  intensely  irritating,  producing 
redness  and  prickling  in  the  skin,  and  a  burning  sensation  in  the  month 
and  throat. 


442  SUBSTANCES  ACTING  AFTER   ABSORPTION 

The  Nervous  Symptoms  arc  supposed  by  some  to  be  due  to  a  direct 
action  on  the  central  ncrxons  system,  but  arc  to  be  ascribed  rather  to 
a  concHtion  of  collapse  produced  indirectly  through  the  action  on  the 
abdominal  organs. 

The  influence  of  colchicine  on  the  Kidneys  varies,  for  in  some  cases 
complete  anuria  is  produced  for  many  hours,  while  in  others  the  urine 
is  slightly  increased.  The  constituents  of  the  urine  are  not  materially 
altered  by  ordinary  therapeutic  doses  of  colchicum,  and,  in  particular, 
the  uric  acid  shows  no  constant  change  in  amount.  In  animals  bloody 
urine  is  sometimes  passed  after  colchicine. 

In  poisoning  with  colchicine  the  leucocytes  are  at  first  reduced  in 
the  peripheral  circulation,  but  afterwards  increase  to  beyond  the 
normal  number. 

All  of  these  symptoms  are  exactly  those  caused  by  a  large  number 
of  poisons,  including  some  of  the  bacterial  toxins  and  the  heavy 
metals.  ]\Iany  local  irritants  when  injected  into  the  blood  or  when 
absorbed  from  the  subcutaneous  tissue  or  the  alimentary  canal,  exer- 
cise an  immediate,  local  action,  which  betrays  itself  in  pain  or 
ecchymosis  and  swelling  at  the  point  of  injection,  but  these  symptoms 
pass  off  in  a  short  time  and  the  animal  becomes  apparently  normal 
for  many  hours  or  even  days.  At  the  end  of  this  time,  howe\er, 
symj^toms  begin  to  de\-elop  at  two  points — in  the  alimentary  canal 
and  in  the  kidneys.  The  reason  probably  is  that  the  poisons  are 
excreted  at  these  points  and  are  either  freed  from  some  harmless  com- 
bination in  which  they  have  circulated  in  the  tissues,  or  perhaps 
collect  in  larger  quantities  in  the  excretory  organs.  At  any  rate, 
irritation  and  later  acute  inflammation  are  set  up  at  these  points. 
At  first  the  irritation  excites  only  diarrhoea  and  diuresis,  but  as  it 
goes  on,  gastro-enteritis  and  anuria  or  hematuria  may  be  produced. 
The  symptoms  from  the  intestine  and  kidney  may  not  l)e  equally  well 
marked;  at  one  time  the  one  becomes  inflamed  while  the  other  is  only 
subjected  to  mild  stimulation,  while  at  other  times  both  are  the  seat 
of  acute  inflammation.  The  inflammation  of  the  bowel  produces  a 
condition  of  collapse,  which  is  seen  also  in  various  intestinal  diseases, 
such  as  cholera.  Sometimes  the  poisons  (and  also  cholera)  produce 
no  very  marked  symptoms  of  gastro-intestinal  disorder,  but  rather 
those  of  collapse,  but  there  is  no  reason  to  believe  that  the  collapse  is 
due  to  any  direct  action  on  the  central  nervous  system. 

A  number  qf  colchicine  derivatives  have  been  examined  by  Fiihner,  who 
finds  tliat  colchiceine  has  little  action  and  that  oxycolchicine  is  equally  inactive 
in  iiiMiiimaLs,  but  is  very  poisonous  in  frogs,  in  which  it  i)rolongs  the  muscle 
curve  in  the  same  way  as  veratrine  and  also  causes  strychuine-Uke  coiivulsions. 
Colchicine  itself  only  acts  in  tlie  frog  after  a  latent  period  extending  over  some 
weeks,  as  a  general  rule. 

Preparations. 

Colchici  Cormus  (U  8   P.,  U.  P.),  the  conn  or  bulb  of  Colchicum  autumiialc, 
containiiiii;  OM.')  per  cent,  of  colchicine,  0.2")  (!.  (4  grs.). 
E.rlrdcliiiii  Culcliici  (B.  P.),  \-\  gr. 


PIIENYLQUINOLINE  CARBONIC  ACID  443 

ViNUM  C'oT.CHici  (B.  P.)  (lO-.SO  mills.). 

Colchici  Semen  (U.  S.  P.),  Colchici  Semina  (B.  P.),  the  seed  of  Colchicmn 
luiluiinialc,  coulaiiiiiis;-  0.55  per  cent,  of  colchicine,  0.2  G.  (3  grs.). 

Fiuuh'.rtradiim  Colchici  Scminis  (U.  S.  P.),  0-2  c.c.  (3  miiis.). 

Tindura  Colchici  Seminis  (U.  S.  P.),  2  c.c.  (30  inins.). 

Tinctur a  Colchici  (B.  P.),  5-15  mins. 

Colchicina  (U.  S.  P.)  (CasHzsNOe),  an  alkaloid  obtained  from  colchicum, 
pale  yellow  in  color,  with  a  bitter  taste  and  characteristic  odor;  soluble  in  22 
l)arts"of  water  and  in  alcohol.     Dose,  0.5  mg.  (rk  gr.). 

Therapeutic  Uses. — Colchicum  has  long  been  used  in  gout  on  purely 
empirical  grounds.  In  fact,  the  pathology  of  gout  is  so  obscure  that 
no  rational  treatment  for  it  can  be  looked  for  at  the  present  day,  and 
the  efficacy  of  colchicum  in  this  disease  can,  therefore,  be  argued 
solely  from  clinical  experience.  There  is  no  doubt  that  the  pain  and 
inflammation  around  the  joint  in  an  acute  attack  of  gout  are  relieved  by 
colchicum,  often  without  any  other  obvious  effect,  but  sometimes  only 
after  enough  has  been  given  to  cause  some  diarrhoea.  In  the  intervals 
between  the  acute  attacks,  colchicum  does  not  appear  to  have  any 
beneficial  effect,  and  it  is  not  clear  that  continued  treatment  wards  off 
the  attacks.  The  uric  acid  excretion  is  not  altered  by  colchicum  treat- 
ment in  gout,  nor  in  health.  And  though  some  investigators  have 
stated  that  the  excretion  of  endogenous  uric  acid  is  increased  by  col- 
chicum, while  that  deriA'ed  from  the  food  remains  unaffected,  this  has 
not  been  established.  The  failure  to  explain  the  action  of  colchicum 
in  gout,  by  changes  in  the  uric  acid  elimination  or  in  any  other  way, 
does  not  diminish  the  importance  of  the  clinical  evidence  that  it  is 
beneficial  in  this  disease,  but  merely  indicates  that  further  research  is 
necessary  before  the  problem  can  be  solved. 

Bibliography. 

Jacohj.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxvii,  p.  119. 

A''.  Paton.     Brit.  Med.  Journ.,  1886,  i,  p.  377,  and  Journ.  of  Anat.  u.  Phy.s.,  xx,  p.  2G7. 

Fawcett.     Guy's  Hospital  Reports,  lii,  p.  115. 

Dixon  and  Maiden.     Journ.  of  Physiol.,  xxxvii,  p.  50. 

Fuhner.     Arch.  f.  exp.  Path.,  Ixxii,  p.  228. 

XXVI.     PHENYLQUINOLINE  CARBONIC  ACID   (ATOPHAN). 

A  number  of  compounds  of  the  type  of  quinoline  carbonic  acid  have 

been  shown  by  Nicolaier  to  increase  the  amount  of  uric  acid  excreted 

in  the  urine  in  a  remarkable  way;  among  these  the  phenyl-quinoline 

carbonic  acid  is  the  most  efficient  and  has  been  introduced  into  medicine 

under  the  name  of  atophan, 

CH  c— COOH 

c 


HC/        \/        \CH 


HC\         /\         /C— Cr,Hs 
C 


CH 


444  SUBSTANCES  ACTING  AFTER  ABSORPTION 

A  nearly  related  substance,  the  ethyl  ester  of  a  methyl-atophan  is 
issued  under  the  name  of  Novatoj)han. 

Atophan  may  be  taken  in  large  quantities  (100  grs.)  without  any 
ob\'ious  symptoms,  but  considerably  smaller  doses  (30  grs.)  may  suffice 
to  increase  the  uric  acid  of  the  urine  threefold;  in  other  cases  the 
augmentation  is  not  so  great,  but  it  is  almost  always  40  or  50  per  cent. 
The  urine  is  but  little  changed  in  amount  but  is  often  turbid  when 
passed,  and  deposits  ciuantities  of  urates  on  standing;  this  turbidity 
may  appear  within  forty-five  minutes  of  the  administration  of  atophan. 
No  other  constituent  of  the  urine  is  altered  appreciably  in  amoinit. 
This  increased  elimination  of  urates  and  uric  acid  occurs  in  persons 
on  ordinary  diet  and  also  on  a  purine-free  diet,  in  which  the  uric  acid 
excreted  can  arise  only  from  the  tissue  change.  When  ato{)han  is  given 
for  one  day  only,  the  excretion  of  uric  acid  rises  innnediateh',  and  the 
following  day  it  sinks  below  the  normal  amount,  as  if  the  first  large 
excretion  had  exhausted  the  supply.  When  it  is  given  continucnisly  for 
some  time,  the  excretion  falls  rapidly  after  the  first  day  and  may  reach 
the  normal  or  even  below^  it  on  subsequent  days;  very  often  however, 
more  uric  acid  is  excreted  each  day  than  normally,  although  the  marked 
excretion  attained  at  first  is  not  repeated. 

The  more  rapid  excretion  of  uric  acid  is  attended  by  a  fall  in  the 
uric  acid  content  of  the  blood  (Folin  and  Lyman).  The  action  is 
thus  a  direct  one  on  the  kidney,  which  is  more  readily  ])ermeated  by 
the  urates,  so  that  those  previously  retained  in  the  blood  through  the 
difficulty  attending  their  elimination  by  the  kidney,  now  escape  in  the 
urine.  The  kidney  is  changed  only  in  relation  to  the  uric  acid,  and 
the  other  constituents  of  the  urine  thus  remain  unaltered.  The  rapid 
removal  of  the  urates  of  the  blood  and  tissues  appears  often  to  increase 
the  formation  of  uric  acid  in  the  body,  for  the  continued  treatment 
with  atophan  is  attended  by  an  abnormally  large  amount  of  uric  acid 
in  the  urine  even  when  it  extends  to  weeks  in  tluration.  And  it  has  been 
found  that  under  atophan  more  uric  acid  is  eliminated  in  the  urine 
from  a  given  quantity  of  nucleinic  acid  than  can  be  obtainc^l  in  ordinary 
circninstances.  The  formation  of  uric  acid  in  the  organs  is  thus  faxored 
by  the  atophan  treatment,  but  this  appears  not  to  be  due  to  any  direct 
action,  but  to  be  the  result  of  the  rapid  excretion,  which  leads  to  a  fall 
in  the  urates  of  the  blood  and  thus  makes  room  for  fresh  urates  from 
the  organs;  i)ossibly  the  reduced  iimount  of  urate  in  the  blood  may 
change  the  direction  of  decomi)osition  of  nucleinic  acid,  some  which 
would  normally  be  excreted  as  urea,  now  following  the  alternative 
I)ath  to  end  as  uric  acid.  All  the  evidence  points  to  atophan  increasing 
elimination  by  the  kidney  rather  than  to  any  direct  inlluencc  on  uric 
formation,  th(nigh  this  is  by  no  means  generally  accepted.  Abl  finds 
that  calcium  and  atropine  lessen  the  excretion  of  uric  acid  untler 
atophan.  Atophan  appears  to  undergo  decomposition  in  the  tissues 
for  the  most  part,  though  some  ai)pears  in  the  urine  unchanged. 

Atophan,  ('icIInNOj,  (uno(Iici;il)  forms  sniiill  colorless  cr\st;ils  with  a 
bitter  taste,  ;ilmost  insoluble  in  water  but  soluble  in  alkalies  and  acids. 


SAPONIN,  SAPOTOXIN  AND  SOLAN  IN  E  445 

Dose,  2-4  G.  (oO-GO  grs.)  per  day  in  cIi\i(Jcd  doses,  given  as  powder  or 
tablets. 

Atophan  lias  l)cen  used  in  gout  chiefly,  in  which  it  increases  the  uric 
acid  elimination  in  the  same  way  as  in  health  and  does  not  induce  any 
other  symptom.  This  free  removal  of  uric  acid  appears  to  be  of  benefit 
in  the  disease  and  several  observers  state  that  the  deposits  of  urates 
(tophi)  are  lessened  in  size  and  the  chronic  inflammation  of  the  joints 
is  relieved;  others  have  observed  less  benefit  and  deny  that  uric  acid 
deposits  are  reabsorbed  under  atophan.  There  seems  no  doubt  that 
atophan  fails  to  relieve  the  pain  and  inflammation  of  an  acute  attack 
in  the  way  which  has  given  colchicum  its  reputation  in  this  disease. 

Bibliography. 

Nicolaier.     Deutsch.  Arch.  f.  klin.  Med.,  xciii. 
Slarkenstein.     Arch.  f.  exp.  Path.  u.  Pharm.,  Ixv,  p.  177. 
Bauch.     Arch.  f.  Verdauungsk.,  xvii.    Erganzh.,  p.  186. 
Frank  and  Przedborski.     Arch.  f.  exp.  Path.,  Ixviii,  p.  349. 
Folin  and  Lyynan.     Journ.  of  Pharmacology,  iv,  p.  539. 
Ahl.     Arch.  f.  exp.  Path.  u.  Pharm.,  Ixxiv,  p.  119. 

XXVII.      SAPONIN,   SAPOTOXIN  AND  SOLANINE. 

This  group  comprises  a  series  of  glucosides  which  are  very  \\idely 
distributed  in  plants  and  which  resemble  each  other  in  their  chemical 
composition  as  far  as  that  is  known  and  also  in  their  action  on  li\'ing 
tissues.  Kobert  has  found  that  many  of  them  may  be  arranged  in  a 
chemical  series  CnH2n-80io.  Some  have  an  acid  reaction  and  form 
salts  with  the  alkalies,  while  all  possess  the  characteristic  glucosidal 
reaction,  being  decomposed  by  acids  or  ferments  into  sugars  and 
unknown  inactive  substances.  The  most  poisonous  among  them  are 
designated  by  the  general  term  of  Sapotoxins,  while  Saponin  may  be 
used  to  include  the  less  active  and  the  wholly  innocuous  members  of  the 
group.  ]\Iany  plants  contain  several  of  these  bodies  and  their  isolation 
is  very  difficult. 

These  glucosides  reduce  the  surface  tension  of  water  to  a  very  marked 
degree,  and  even  dilute  solutions  form  froths  like  soap  when  shaken  up. 
From  this  property  the  plants  deri^'e  their  popular  names  of  soap-root 
or  soap-bark.  The  reduction  of  the  surface  tension  also  explains  the 
■  property  of  holding  insoluble  bodies  in  suspension  which  is  common  to 
the  series.  The  saponins  have  a  peculiar  affinity  for  lecithin  which 
they  dissolve,  while  cholesterin  forms  an  insoluble  chemical  compound 
with  many  of  them. 

Saponins  or  sapotoxins  are  found  in  about  150  species  of  plants. 
The  chief  of  these  are: 

Quillaja  saponaria,  or  soapbark  (containing  quillaja-sapoto.vin  and 
quillajac  acid). 

Saponaria  officinalis,  or  soapwort  (sapnrubrin  and  saponin). 

Cyclamen  Europeum,  or  sowbread  (cyclamin). 

Polygala  senega  {senegin  and  polygalic  acid). 


440  SUBSTANCES  ACTIXd  AFTER   ABSORI'TION 

Agrostemma  githago,  or  corncockle  {(Ujrostemma-sapoto.rin  and  (wid). 

Gypsophila  struthium  and  other  s])ecie.s  (gyp.SDphihi-.sapjfoxiii). 

Chamselirium  luteum,  or  hla/inji;  star  {chaiimlirhnn-sapfdnxln). 

Smilax,  various  species,  including  those  known  as  sarsaparilla  {mr- 
sapoiiiii,  sarsapariUa-sapomn  and  imrillin  or  smilacin). 

In  addition  to  the  plants  which  owe  their  action  to  the  presence 
of  these  bodies,  a  number  of  drugs  contain  saponins  along  with  other 
more  important  principles.  Thus  an  almost  inactive  saponin  islicji- 
tonin)  is  met  with  in  digitalis,  and  similar  saponins  occur  in  several 
others  of  the  digitalis  series,  although  they  have  not  yet  been  isolated; 
helleborein  appears  to  stand  midway  between  the  true  digitalis  glucosides 
and  the  saponins  in  its  action. 

The  most  poisonous  sapotoxins  are  those  of  (piillaja,  agrostemma, 
and  gypsophila,  quillajac  acid  and  cyclamin.  Senegin  is  only  about 
one-tenth  as  poisonous  as  ciuillaja-sajjotoxin,  and  some  saponins  may 
be  regarded  as  harmless  when  taken  in  ordinary  quantity. 

Another  body  closely  resembling  the  saponins  in  action  is  Solan ine, 
a  glucosidal  alkaloid  found  in  many  species  of  Solanum,  such  as  S. 
nigrum  (black  nightshade),  S.  dulcamara  (bittersweet),  S.  tuberosum 
(potato),  and  probably  in  some  species  of  Scopola.  Solanine  breaks 
up  on  being  heated  with  acids  into  sugar  and  a  base,  Solan idinc,  which 
retains  the  poisonous  action.  Some  interest  attaches  to  solanine  from 
its  having  been  held  responsible  for  some  instances  of  widespread 
poisoning  from  the  use  of  potatoes.  But  it  is  now  known  that  the 
symptoms  arose  from  putrefactive  bacteria  and  their  products,  and 
that  solanine  is  never  present  in  the  tuber  of  the  potato  in  sufficient 
quantity  to  be  noxious. 

Action. — The  sapotoxins  have  a  harsh,  acrid,  taste,  and  when  swal- 
lowed provoke  nausea  and  often  vomiting,  with  pain  and  colic,  and  less 
frequently  diarrhoea.  They  are  not  absorbed  by  the  normal  epitlu>lium 
of  the  alimentary  canal,  and  seem  to  undergo  decomposition  in  the 
bowel,  and  therefore  fail  to  produce  general  symptoms.  Thus  pigs 
feed  with  avidity  on  Cyclamen  and  are  unharmed  by  it  unless  some 
lesion  of  the  intestine  is  i)resent.  The  unbroken  skin  is  not  affected 
by  a  single  ai)plication  as  a  general  rule,  but  when  they  are  ai)i)lied 
repeatedly  or  rubbed  in  as  ointment  they  cause  irritation  and  pustules. 
Absorption  is  extremely  slow  from  the  subcutaneous  tissues,  in  which 
they  act  as  irritants,  however,  and  ])roduce  inflannnation  and  supi)ura- 
tion.  The  sapotoxin  derived  from  Agrostemma  dill'ers  from  the  others 
in  being  absorbed  fairly  rapidly  from  the  alimentary  canal  and  from 
the  subcutaneous  tissues,  so  that  more  dangerous  symptoms  may  arise 
from  it  than  from  the  other  members  of  the  series. 

When  these  bodies  are  injected  directly  into  the  bloodxessels,  they 
indnce  nnich  more  characteristic  changes,  which  very  often  i)rove 
fatal  after  a  longer  or  shorter  inter\;d.  Wry  large  (piantities  thus 
inj(H'te<l  may  kill  animals  within  a  few  minut»'s  from  respiratory 
paralysis,  and  no  characteristic  appearances  are  to  be  found  post- 
niortcui.        Smaller   doses   induce   depression,  loss   of  appetite,  some- 


SAPONIN,  SAPOTOXIN  AND  SOLAN  IN  E  447 

times  \oniiting  and  diarrhoea,  general  weakness  and  collapse,  with 
some  dyspnoea  and  irregular,  feeble  pulse.  Weak  convulsions  appear 
I'ust  before  the  failure  of  the  respiration,  while  the  heart  continues 
to  contract  for  some  minutes  longer.  In  these  cases  ecchymoses  are 
found  in  the  serous  membranes,  pericardium,  pleura  and  peritoneuin^ 
and  occasionally  in  the  kidneys.  Endocarditis  has  been  observed  in 
some  instances,  but  the  most  important  alterations  occur  in  the 
stomach  and  intestines,  the  mucous  membrane  of  which  is  swollen 
and  congested  and  contains  numerous  blood  extravasations.  The 
lymphatic  glands  of  the  abdominal  cavity  are  also  swollen  and  con- 
gested and  often  filled  with  haemorrhages.  Occasionally  the  kidneys 
are  found  to  contain  numerous  blood  casts,  filling  the  lumen  of  the 
tubules,  and  in  these  cases  albumin  and  hemoglobin  appear  in  the 
urine  before  death;  these  are  more  often  elicited  by  solanine  than  by 
the  sapotoxins.  In  Cyclamen  poisoning  (from  intravenous  injection) 
htemoglobinuria  is  one  of  the  earliest  symptoms. 

The  property  of  dissolving  lecithin  which  is  characteristic  of  this 
series  renders  them  poisonous  to  living  tissues  when  they  come  in  contact 
with  them  in  sufficient  concentration.  On  the  other  hand,  cholesterin 
deprives  them  of  toxicity  by  forming  inactive  cholesterides,  but  as  a 
general  rule  the  cholesterin  is  not  in  sufficient  amount  to  neutralize 
them  completely.  Their  irritant  action  on  the  mouth,  throat  and 
stomach  is  the  cause  of  the  nausea  and  vomiting  observed  when  they 
are  administered  in  this  way,  and  they  cause  sneezing  and  coughing 
from  the  same  action  in  the  nose  and  throat.  On  other  mucous  mem- 
branes, such  as  the  conjunctiva,  and  in  wounds,  they  cause  similar 
irritation  and  inflammation,  which  may  be  followed  by  suppuration. 
A  form  of  local  anesthesia  often  follows  this  irritation,  the  termina- 
tion of  the  sensory  ner^•es  apparently  being  benumbed,  but  the  pre- 
liminary irritation  precludes  their  use  for  this  purpose. 

"When  the  individual  organs  are  exposed  to  the  action  of  saponin 
bodies  by  the  direct  application  of  solutions  to  them,  a  similar  poison- 
ous action  is  elicited.  Muscle  contracts  more  weakly  even  in  dilute 
solutions,  is  eventually  entirely  paralyzed,  and  is  altered  in  structure, 
the  transverse  strise  of  voluntary  muscle  and  of  the  heart  becoming 
very  indistinct.  Nerves  exposed  to  solutions  are  also  paralyzed  in 
the' same  way,  and  the  movements  of  cilia  cease  at  once  when  they  are 
exposed  to  sapotoxin  bodies.  The  blood  undergoes  characteristic 
changes  when  it  is  acted  on  by  saponin  either  in  the  vessels  or  in  the 
test-tube.  The  red  blood  cells  undergo  rapid  destruction  and  the 
hemoglobin  is  freed  in  the  plasma.  Even  one  part  of  cyclamin  added  to 
100,000  parts  of  diluted  blood  completely  lakes  the  red-blood  cells, 
while  hen:!Oglobin  appears  in  the  serum  when  considerably  less  poison 
is  addded.  The  other  saponin  bodies  act  less  powerfully  in  this  direction 
than  cyclamin,  but  still  i)roduce  distinct  solution  of  the  substance  of 
the  red  corpuscles.  When  a  saponin  is  injected  into  the  blood  of  a 
li\ing  animal  this  destruction  of  the  red-blood  cells  takes  place  to  some 
extent,   and  the  plasma  contains  hemoglobin,  while  the  blood  cor- 


448  SUBSTANCES  ACTING  AFTER  ABSORPTION 

puscK-s  arc  considerably  diminislicd  in  number.  This  liteniolytic 
action  is  not  the  result  of  changes  in  the  luemofilobin,  but  is  due  to  the 
dissolution  of  the  stroma  of  the  corpuscles,  which  releases  the  h;i?mo- 
globin.  The  saponins  have  a  strong  solvent  action  on  the  lecithin  of  the 
stroma  and  its  removal  leads  to  the  disintegration  of  the  cell.  This 
solvent  action  occurs  more  readily  when  the  blood  cells  are  suspended 
in  normal  salt  solution  than  in  the  plasma  or  serum,  because  the  choles- 
terin  of  the  serum  forms  inactive  compounds  with  the  saponins.  Even 
when  the  h.iemoglobin  in  the  corpuscles  is  coagulated  and  saponin  fails 
to  induce  laking,  the  structure  of  the  corpuscle  is  altered,  as  is  shown 
by  its  reaction  to  salts  (Stewart) . 

'  The  frog's  heart  perfused  with  sapotoxins  is  arrested  in  systole  in  the 
same  way  as  by  digitalis,  and  the  mammalian  heart  is  also  weakened 
when  saponin  is  injected  intravenously,  though  it  continues  to  beat 
after  the  breathing  has  ceased.  The  central  nervous  system  is  also 
susceptible  to  the  changes  in  the  lecithin  in  the  nerve  cells,  and  the 
failure  of  the  respiratory  centre  is  the  cause  of  death.  In  many  experi- 
ments the  collapse  from  the  irritation  of  the  alimentary  canal  prwes 
fatal,  but  in  others  in  which  large  doses  are  immediately  fatal  the  poison 
is  believed  to  act  directly  on  the  nerve  cells,  whose  acti\ity  is  suspended 
by  changes  in  the  distribution  of  the  lipoids  similar  to  that  under 
the  alcohol-chloroform  group.  A  similar  central  nervous  action  may 
explain  experiments  in  which  only  small  quantities  of  the  poison  htu'e 
been  injected,  but  in  which  the  animal  dies  after  a  few  days,  presenting 
no  distinct  symptoms  except  general  weakness  and  depression. 

The  sapotoxins  are  poisonous  to  invertebrates  apparently,  unless 
they  are  protected  by  a  shell,  through  which  the  poisons  cannot  pene- 
trate. Thus  the  amoeba  and  other  simple  organisms  cease  their  mo^•c- 
ments,  while  intestinal  worms  are  first  excited  and  then  paralyzed  in 
the  presence  of  some  of  the  group. 

I'aust  has  recently  shown  that  oleic  acid  has  the  same  haemolytic  action 
as  the  saponin  substances,  and  that  some  forms  of  anaemia  are  due  to 
the  red  blood  cells  being  destroyed  by  oleic  acid  absorbed  in  excess. 


Preparations. 

Quillaise  Cortex  (B.  P.),  Panama  bark,  Soap  bark,  the  inner  hark  of  Quillaja 
s;iiH)ii;iri;i. 

Sarsaparilla  (U.  S.  P.),  the  root  of  Smilax  medica  and  other  species  of  Snulax. 

Fluidcxlmclum  Sorsaparillce  (U.  S.  P.),  2  c.c.  (30  mins.). 

Fluidcxlrnctum  Sarsaparilla;  Compositum  (U.  S.  P.)  contains  sassafras,  liquo- 
rice, and  mezereum.    2  c.c.  (30  mins.). 

Syrvpus  Sorsaparillce  Compositus  (U.  S.  P.),  contains  liquorice,  senna  and 
the  oils  of  sassafras,  anise  and  wintergreen.     16  c.c.  (4  fl.  drs.). 

Senega  (U.  8.  P.),  Senegse  Radix  (B.  P.),  the  root  of  Polygala  Senega.  1  G. 
(15  grs.). 

Syrupiis  Seneg(v  (U.  S.  P.),  4  c.c.  (1  fl.  dr."). 

Tindura  Seneqm  (B.  P.),  \-\  fl.  dr. 

Infiisuin  Scnc{i<c  (B.  P.),  ^-1  fl.  oz. 


I'liUSSIC  ACID  449 

Therapeutic  Uses. — The  drugs  of  this  .uroup  arc  all  ciuitc  suixtIIuous. 
They  may  he  used  to  increase  the  bronchial  secretion  in  cough  through 
the  nausea  caused  by  their  slight  irritant  action  in  the  stomach,  Init 
they  ha\-e  no  advantages  over  such  drugs  as  ipecacuanha;  the  syrup 
of  senega  is  often  prescribed  in  expectorant  mixtures  for  this  purpose. 
Sarsaparilla  has  been  supposed  to  have  an  obscure  action  on  the  nutrition, 
and  has  some  reputation  in  the  treatment  of  syphilis,  but  there  is  no 
reason  to  believe  that  it  is  of  any  service  here  or  in  any  other  condition, 
although  it  may  be  used  as  a  vehicle  for  the  administration  of  mercury 
and  iodide  of  potassium.  Quillaja  has. been  used  to  some  extent  as  an 
expectorant,  more  largely  to  form  emulsions  and  to  suspend  insoluble 
powders.  Its  irritant  action  ought,  however,  to  preclude  its  use  for 
this  purpose.  It  is  frequently  stated  that  members  of  the  sapotoxin 
series  are  antidotes  in  digitalis  poisoning,  but  this  is  incorrect. 

Bibliography. 

Robert.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxiii,  p.  233. 

Stewart.     Journ.  of  Exp.  Mod.,  vi,  p.  257;    Jouru.  Med.  Research,  viii,  p.  268. 
Hedon.     Arch,  internat.  de  Pharmacodyn.,  viii,  p.  381;    ix,  p.  393. 
Ransom.     Deutsch.  med.  Woch.,  1901,  p.  194. 

Pachorukow,  Ailass  u.  Tufanow,  Kruskal,  Kiwull,  Schuh.  Arbeiten  a.  d.  Phann. 
Inst,  zu  Dorpat. 

Pescucci.     Hofmeister's  Beitriige,  vi,  p.  553. 

Brandl.     Arch.  f.  exp.  Path.  u.  Pharm.,  Hv,  p.  245;    hx,  pp.  245,  299. 

Bruere.     Journ.  of  Med.  Research,  viii,  p.  362. 

Yagi.     Arch.  f.  exp.  Path.  u.  Pharm.,  Ixiv,  p.  141. 

Perles.     Ibid.,  xxvi,  p.  88.     (Solanine.) 

Weil.     Arch.  f.  Hygiene,  xxxviii,  p.  330.     (Solanine.) 

XXVm.    PRUSSIC  ACID. 

Prussic,  or  hydrocyanic,  acid  differs  entirely  from  the  other  acids  in 
its  pharmacological  action,  and  has  therefore  to  be  described  apart 
from  them. 

The  pure  acid  is  scarcely  ever  seen  save  in  the  chemical  laboratory, 
and  is  an  extremely  dangerous  body  to  handle,  as  it  is  very  volatile 
and  when  inhaled  may  produce  death  within  a  few  seconds.  It  is 
generally  met  with  in  a  very  dilute  solution,  which  is  formed  by  the 
decomposition  of  one  of  its  salts. 

In  nature,  prussic  acid  occurs  in  the  secretion  of  some  of  the  m;)Tia- 
poda,  and  in  the  decomposition  products  of  a  few  glucosides,  of  which 
Amygdalin  is  the  best  known.  Amygdalin  is  in  itself  practically 
inactive,  but  may  be  decomposed  by  dilute  acids  or  by  a  ferment, 
emulsin,  which  is  generally  found  associated  with  it  in  plants  (see 
p.  62).  Prussic  acid  may  be  formed  from  the  amygdalin  of  the  bitter 
almond  and  the  kernels  of  such  fruits  as  the  apple,  cherry,  plum,  etc., 
and  from  the  bark  and  leaves  of  several  trees  including  the  laurel 
(Prunus  laurocerasus).  A  paste  formed  from  bitter  almonds  has  given 
rise  to  symptoms  from  the  prussic  acid,  but  a  more  dangerous  substance 
is  the  oil  of  bitter  almonds,  which  consists  of  benzaldehyde  and  prussic 
acid  in  a  loose  combination  and  in  very  varying  proportions.  Sweet 
29 


450  SUBSTANCES  ACTING  AFTER  ABSORPTION 

aliiioiids  contain  no  amygdalin  and  are  therefore  harmless.  Laurel 
water  and  the  preparations  of  Virginian  cherry  bark  contain  benzalde- 
hyde  and  prussic  acid  in  too  small  quantity  to  have  any  poisonous 
action.  Several  plants  which  contain  glucosides  similar  to  amygdalin 
have  given  rise  to  poisoning  in  cattle,  probably  from  prussic  acid  being 
freed  from  the  glucosides  in  the  intestine. 

Prussic  acid  and  its  salts  have  practically  the  same  action,  although 
none  of  the  latter  are  so  poisonous  as  the  free  acid.  Cyanogen,  (CN)2, 
also  resembles  prussic  acid  in  its  effects,  but  is  not  so  active. 

Tlie  fcrrocyanides  and  other  doulile  cyanides  arc  in  most  cases  harmless 
hut  other  compounds,  from  which  prussic  acid  is  formed  in  the  organism, 
are  poisonous.  The  organic  combinations  containing  the— CN  radiclejorm 
two  series,  the  Nitriles,  in  which  the  nitrogen  is  trivalent  (e.  g.,  CH3— C=N), 
and  the  Lsoiiitriles,  or  Carbylawines,  in  which  the  alkyl  is  attached  to  the  nitrogen 
(e.  g.,  CH3— N  =  C).  These  compounds  are  all  much  less  poisonous  than  prussic 
acid.'and  the  nitriles  are  said  to  differ  from  it  in  their  effects,  inasmuch  as  the 
chief  symptoms  caused  by  them  arise  from  gastro-intestinal  irritation.  The 
isonitriles  are  more  poisonous  than  the  nitriles  and  resemble  the  acid  more 
closely  in  their  action.  Both  nitriles  and  isonitriles  give  rise  to  the  formation 
of  prussic  acid  in  the  tissues. 

Symptoms  and  Action. — Prussic  acid  first  stimulates  and  then  para- 
lyzes the  central  nervous  system  in  mammals,  but  it  acts  on  so  many 
forms  of  living  matter  that  it  merits  the  designation  of  a  general 
])r()toplasm  poison.  The  fatal  dose  in  man  is  believed  to  be  about 
0.05-0.08  G.  (1-1|  gr.)  of  the  pure  acid,  certainly  a  much  larger  quan- 
tity than  is  fatal  in  cases  of  poisoning  with  some  of  the  alkaloids  and 
glucosides.  Prussic  acid  acts  much  more  rapidly  than  these,  however, 
and  has  thus  gained  its  reputation  of  being  the  most  dangerous  of 
poisons. 

After  very  large  doses  in  mammals,  there  may  be  jiractically  no 
symptoms;  the  animal  falls  to  the  ground  with  a  slight  convulsive 
movement  or  a  scream,  and  death  follows  in  a  few  seconds  from  simul- 
taneous arrest  of  the  heart  and  respiration. 

In  smaller  quantities  prussic  acid  has  a  bitter,  acrid,  burning  taste, 
which  is  accompanied  by  salivation,  and  is  followed  by  numbness  in 
the  mouth  and  throat.  A  sensation  of  warmth  in  the  stomach  is 
followed  by  nausea  and  vomiting,  confusion  and  headache,  dyspnoea, 
slow  ])ulse  and  general  nuiscular  weakness.  The  pupils  are  widely 
dilated  and  the  eyeballs  protrude,  as  generally  occurs  in  asphyxia. 
Unconsciousness  follows,  and  then  violent  convulsions,  which  pass  into 
j)aralysis  with  involuntary  evacuation  of  the  contents  of  the  bladder 
and  i)owels;  the  respiration  becomes  extremely  slow  and  eventually 
ceases,  while  the  heart  contiiuies  to  beat  for  some  time  afterward. 

In  frogs,  no  convulsions  occur,  the  symi)toms  pointing  to  a  paralysis 
of  the  central  nervous  system  without  i)rcliminary  stinudation,  except 
in  that  the  res])iration  is  somewhat  (juick  and  dysi)naMC. 

In  niaminals  the  Central  Nervous  System  is  first  stimulated  and  then 
paral\zcd.   but    the   action   seems  to   be  dcv(>lopcd   more   fidl\    in   the 


PRUSSIC  ACID 


451 


incdiilla  oblongata  and  lower  parts  of  the  brain  tlian  in  the  cerebral 
cortex,  for  the  convulsions  resemble  those  produced  by  stimulation  of 
the  hind-brain,  although  the  subsequent  paralysis  seems  to  include  all 
parts  of  the  central  axis. 

The  peripheral  Muscles  and  the  Nerves  are  weakened  and  eventually 
paralyzed  when  suspended  in  an  atmosphere  of  the  gas,  but  they  are 
not  affected  in  poisoning;  the  nerves  are  more  readily  poisoned  than 
the  muscles.  When  prussic  acid  in  solution  is  applied  locally  to  the 
Skin  it  produces  numbness  and  partial  loss  of  sensation,  but  this  does 
not  follow  in  general  poisoning. 

Fig.  62 


Tracing  of  the  movements  of  the  diaphragm  (respiration)  of  the  rabbit  under  a  large 
but  not  fatal  dose  of  cyanide  of  potassium  injected  intravenously.  A-B,  normal  respiration. 
At  B  1  mg.  injected;  the  respiratory  movements  are  much  larger.  At  C  recovery.  Note 
the  short  duration  of  the  stimulation. 


The  Respiration  is  rendered  quicker  and  deeper  by  the  injection  or 
inhalation  of  small  quantities  of  prussic  acid.  After  larger  quantities, 
the  acceleration  is  often  interrupted  by  a  prolonged  pause  after  which 
the  breathing  returns  spontaneously.  In  fatal  poisoning  no  such  return 
occurs,  and  after  very  large  doses  the  breathing  may  cease  within  a 
few  seconds.  These  changes  are  produced  by  primary  stimulation  and 
subsequent  paralysis  of  the  medullary  centre. 

The  Circulation  is  altered  mainly  through  the  action  on  the  central 
nervous  system,  although  prussic  acid  also  acts  directly  on  the  heart. 
The  stimulation  of  the  inhibitory  centre  generally  slows  the  pulse, 
but  this  is  accompanied  by  a  very  considerable  rise  in  blood-pressure 
from  increased  activity  of  ,the  vaso-constrictor  centres.  Later,  the 
blood-pressure  falls,  from  the  depression  of  the  vasomotor  centre,  but 
the  heart  is  now  directly  affected,  and  its  movements  therefore  remain 
somewhat  slow. 


452  SU/iSTANCKS  ACTING  AFTER  ABSORPTION 

Nutrition, — Besides  its  specific  action  on  the  central  nervous  s^'stem, 
prussic  acid  exercises  a  depressant  action  on  protoplasm  in  general. 
Both  plants  and  animals  are  retarded  in  their  movements  and  in  their 
nutritive  processes  by  its  presence,  although  they  may  recover  and  show 
no  subsequent  deterioration,  provided  the  poison  acts  only  during  a 
short  time  and  in  sufficient  dilution.  For  example,  the  devel()i)ment 
of  seeds  is  hindered  by  the  presence  of  prussic  acid,  but  proceeds  when 
it  is  withdrawn;  yeast  cells  cease  their  activity,  and  the  insectivorous 
plant  Drosera  no  longer  moves  its  tentacles  in  the  presence  of  cyanides 
or  prussic  acid  (Darwin).  This  action  in  plants  is  probably  due  to  the 
poison  arresting  the  activity  of  the  ferments  and 'the  respiration  of  the 
cells,  for  Schroeder  finds  that  in  moulds  the  oxidation  processes  are 
arrested  by  prussic  acid,  no  carbonic  acid  being  given  off  nor  oxygen 
absorbed. 

The  effects  of  prussic  acid  on  the  mammalian  tissues  have  been 
examined  by  Geppert  in  a  long  and  careful  research.  He  found  that 
the  oxygen  absorbed  by  the  tissues  was  much  lessened  by  it;  even 
during  the  most  powerful  convulsions  after  prussic  acid,  the  absorption 
of  oxygen  is  often  distinctly  lower  than  in  the  normal  resting  animal 
and  the  carbonic  acid  formed  by  the  tissues  falls  correspondingly. 
Geppert  proceeded  to  prove  that  the  imperfect  oxidation  is  due  to 
the  tissues  being  unable  to  absorb  the  oxygen  brought  to  them  by  the 
blood  cells;  that,  in  fact,  a  change  occurs  in  the  protoplasm  which 
retards  the  normal  respiration  of  the  cell.  In  consequence  of  this,  the 
oxyhcTmoglobin  of  the  blood  is  not  reduced  in  the  capillaries,  so  that 
the  venous  blood  has  the  same  bright-red  color  as  the  arterial.  Prussic 
acid  is  rapidly  changed  to  harmless  products  in  the  tissues,  however, 
l)rovided  a  lethal  dose  has  not  been  given,  and  as  this  process  goes  on, 
the  protoi)lasm  recovers  its  oxygen-absorbing  power,  the  expired  air 
becomes  less  rich  in  oxygen  and  richer  in  carbonic  acid,  and  the  venous 
blood  assumes  its  ordinary  dark  color.  The  usual  results  of  imperfect 
oxidation  in  the  tissues  are  seen  in  an  increase  in  the  sugar  and  lactic 
acid  in  the  blood.  Imperfect  oxidation  is  also  the  chief  cause  of  the 
augmented  nitrogen,  urea  and  unoxidized  sulphur  of  the  urine.  But 
some  other  changes  in  the  urine  do  not  seem  to  be  adequately  explained 
by  this  factor  and  may  arise  from  some  hitherto  imrecognized  action 
of  the  poison  (Richards  and  Wallace.) 

The  diminution  in  the  oxygen  absor])tion  l)y  the  tissues  is  appar- 
ently due  to  the  activity  of  the  intracellular  ferments  being  arrested  by 
l)russic  acid,  and  there  thus  seems  to  be  an  entire  correspondence 
between  the  changes  produced  in  the  metabolism  of  plants  and  animals 
by  prussic  acid. 

There  is  a  tendency  to  ascribe  the  whole  action  of  the  cyanides  to 
this  arrest  of  oxidation;  for  exam])le,  it  is  often  stated  that  the  (piick 
breathing  and  the  subsequent  asphyxia  both  arise  from  the  oxidative 
l)rocesses  in  the  respiratory  centre  being  stopi)ed  b\'  the  i)oison.  This 
may  be  true,  Ixit  it  is  by  no  means  proved;  the  elVects  in  the  central 
nervous  svstem  umw  not  be  of  the  same  nature  as  those  described  by 


PRUSSIC  ACID  453 

Geppert,  for  the  arrest  of  respiration  occurs  from  quantities  that  have 
but  httle  efi'ect  in  delaying  the  oxi(Uition  in  the  other  organs. 

Prussic  acid  is  changed  to  sulphocyanides  in  the  tissues,  and  is 
partly  excreted  in  the  urine  in  this  form,  while  part  of  it  undergoes 
further  and  unknown  changes.  This  combination  of  prussic  acid  and 
sulphur  bodies,  such  as  the  proteins,  seems  to  arise  by  simple  chemical 
processes,  without  the  intervention  of  living  protoplasm  being  necessary. 

In  the  living  body  prussic  acid  does  not  form  any  combination  with 
the  heemoglobin  of  the  red-blood  cells,  but  in  the  drawn  blood  it 
appears  to  form  cyanhaunoglobin,  a  loose  combination  which  differs 
slightly  from  oxyhemoglobin  in  its  spectrum  and  is  reduced  with  greater 
difficulty,  so  that  the  blood  retains  its  red  color  longer.  In  cases  of 
poisoning  with  cyanides,  the  dependent  parts  of  the  body  often  present 
a  bright  red  color  instead  of  the  usual  post-mortem  lividity,  and  this 
seems  due  to  the  cyanhtemoglobin  retaining  its  red  color,  while  ordinary 
oxyhi^moglobin  is  reduced.  If  normal  blood  be  brought  in  contact 
with  a  solution  of  peroxide  of  hydrogen,  it  effervesces,  owing  to  the 
liberation  of  oxygen  by  the  peroxidase  ferment,  and  the  peroxide  being 
all  decomposed  in  this  way,  the  oxy haemoglobin  remains  unchanged; 
if,  however,  prussic  acid  be  present,  no  effervescence  occurs,  because 
the  peroxidase  is  rendered  inert,  and  the  haemoglobin  is  at  once  changed 
to  methaemoglobin  from  the  oxidizing  action  of  the  peroxide,  which  is  no 
longer  dissipated. 

Preparations. 

Acidum  Hydrocyanicum  Dilutum  (U.  S.  P.,  B.  P.),  a  2  per  cent,  solution 
formed  from  potassium  ferrocyanide  or  silver  cyanide.  It  is  a  colorless  fluid 
with  a  characteristic  smell  and  taste,  and  ought  not  to  be  kept  long,  as  it  is 
Uable  to  decomposition;  much  of  that  actually  used  in  medicine  is  partially 
decomposed  and  therefore  under  2  per  cent,  in  strength.  Dose,  0.1  c.c.  (1| 
mins.) ;  B.  P.,  2-5  mins. 

A  number  of  other  preparations  contain  prussic  acid,  generally  in  very  variable 
ciuantity.  Thus  in  the  U.  S.  P.  the  preparations  of  bitter  almonds,  except  the 
expressed  oil,  contain  it,  and  the  volatile  oil  is,  in  fact,  dangerous  owing  to  the 
large  proportion  of  prussic  acid  sometimes  present.  Another  series  of  prepa- 
rations containing  it,  though  only  in  minute  quantities,  is  that  of  the  bark 
of  the  wild  cherry,  Prunus  Virginiana.  In  the  British  Pharmacopoeia  the 
bitter  almond,  Virginian  cherry  and  the  cherry-laurel  water  contain  it,  but 
only  in  harmless  quantities.  It  is  also  present  in  the  tincture  of  chloroform 
and  morphine,  B.  P. 

Therapeutic  Uses.— Prussic  acid  might  be  eliminated  from  thera- 
peutics without  loss.  It  was  formerly  applied  to  soothe  itching  surfaces, 
but  is  inferior  to  the  cocaine  series.  It  has  also  had  some  reputation, 
probably  undeserved,  in  the  vomiting  of  pregnancy.  It  was  formerly 
used  extensively  as  a  sedative  in  cough,  but  was  generally  prescribed 
along  with  opium  or  other  narcotics,  and  it  seems  unlikely  that  the 
hydrocyanic  acid  had  any  effect. 

In  Poisoning  with  prussic  acid  or  the  cyanides,  the  treatment  is  that 
of  poisoning  in  general — thorough  evacuation  of  the  stomach,  warmth, 
and  general  measures  against  collapse.  Artificial  respiration  should 
be  resorted  to  when  necessary,  as  a  cyanide  is  comparatively  quickly 


454  SUBSTANCES  ACTING  AFTER  ABSORPTION 

rendered  inactive,  and  the  recovery  is  rapid  when  it  once  sets  in.  The 
intravenons  injection  of  sodinm  sulphide  and  liyposulpliite  has  been 
advised  on  the  theory  that  tlie  comparatively  harmless  sulphocyanide 
would  be  formed,  and  animals  seem  to  be  able  to  survive  an  otherwise 
lethal  dose  when  this  is  done.  This,  however,  like  other  proposed 
antidotes,  is  not  generally  applicable  in  an  emergency,  and  if  prussic 
acid  is  not  fatal  within  a  few  minutes,  recovery  may  be  looked  for  with- 
out any  treatment.  But  in  many  cases  life  is  extinct  before  medical  aid 
can  be  called. 

Bibliography. 

Preyer.     Die  Blausiiure,  Bonn,  1868. 
Zillessen.     Ztsch.  f.  phys.  Chem.,  xv,  p.  398. 
Boehm  u.  Knie.     Arch.  f.  exp.  Path.  u.  Pharm.,  ii,  p.  129. 
Geppert.     Ztschr.  f.  klin.  Med.,  xv,  pp.  208  and  307. 

Robert.      Ueber  Cyanmethcemoglobin  und  den  Nachweis  dor  Blausiiure.      Stuttgart, 
1891.     Lehrb.  d.  Intoxicationen,  2ad  ed.,  pp.  9-1-99. 
Lang.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxiv,  p.  247. 
Pascheles.     Ibid.,  p.  281. 
Bunge.     Ibid.,  xii,  p.  41.     (Cyanogen.) 

Heymanns  el  Masoin.     Arch,  de  Pharmacodynamique,  iii,  p.  359.     (Nitriles.) 
Hunt.     Arch,  internat.  de  Pharmacodyn.  et  de  Therap.,  xii,  p.  447. 
Haldane.     Journ.  of  Phys.,  xxv,  p.  230. 
Richards  and  Wallace.     Journ.  Biol.  Chem.,  iv,  p.  179. 
Loewy,  Wolf,  and  Osterberg.     Biochem.  Ztschr.,  viii,  p.  132. 

XXK.     ASPmOSPERMA,  OR  QUEBRACHO. 

The  bark  of  Quebracho  bianco  (Aspidosperma  quebracho)  contains  a  num- 
ber of  alkaloids  which  are  probably  very  similar  in  chemical  composition  and 
which  seem  to  possess  ahnost  the  same  action.  They  are  Aspidospennine, 
Aspidospermatine,  Aspidosamine,  Hypoquebrachine,  Quebrachine,  and  Quebra- 
chamine.  Another  species  of  Aspidosperma,  Payta,  contains  two  alkaloids, 
Paytine  and  Paytcmine,  of  which  Paytine  resembles  closely  the  Quebracho 
alkaloids  in  its  pharmacological  action.  _ 

These  alkaloids  all  produce  nausea,  but  even  after  large  doses  vonntmg 
does  not  occur  except  after  Aspidosamine.  The  nausea  is  accompanied  by  the 
usual  concomitant  symptoms— salivation,  increased  secretion  of  mucus  in  the 
respiratory  tract,  depression  and  alternately  rapid  and  slow  pulse.  Large 
quantities  often  cause  symptoms  of  central  nervous  stimulation,  tonic  con- 
tractions, and  convulsions.  The  respiration  is  quicker  and  deeper  after  small 
quantities,  but  after  lethal  doses  becomes  slow  and  weak,  and  finally  ceases. 
I'eriodic  respiration  often  oc(;urs  before  the  final  standstill,  a  series  of  deep 
dyspiKjeii!  movements  alternating  with  several  shallow,  insuflicient  ones.  The 
failure  of  the  resi)iration  is  the  cause  of  death  in  mammals,  tlie  heart  con- 
tinuing'to  contract  for  some  time  longer.  Quebrachine  is  the  most  powerful 
of  tli(!se  alkaloids,  aspidospermine  nearly  rivalling  it,  while  quebrachamme  and 
aspidosamine  are  less  active. 

These  symptoms  are  generally  ascribed  to  a  direct  action  on  the  central 
nervous  system,  which  is  first  stimulated  and  then  depressed.  The  chief  seat 
of  action  seems  to  be  the  medullary  centres  and  the  spinal  cord,  although  the 
Ijasal  ganglia  may  also  be  more  or  less  involved.  The  stimulation  of  the  inedul- 
lary  c(!ntres  explains  the  nausea  and  vomiting  and  also  the  changes  in  the 
respiration,  wiiiU;  tlH>  convulsions  tuid  increased  refiex  excitability  point  to  the 
spinal  cord. 

The  terminations  of  the  motor  nerves  in  voluntary  muscles  are  paralyzed 
by  aspid()sainiii(>  and  quebrachine  in  the  frog,  not  by  the  oilier  alkaloids;  but 
ail  (if  them  lessen  the  .strength  of  muscular  tissue  and  eventually  paralyze  it 


QUININE  455 

in  these  animals.  Neither  of  these  results  has  been  observed  to  follow  the 
injection  of  the  alkaloids  in  mammals. 

The  circulation  in  mammals  is  affected  indirectly  through  the  nausea,  and 
large  doses  slow  and  weaken  the  heart  through  a  direct  action  in  addition;  the 
blood-pressure  falls  from  depression  of  the  vasomotor  centre.  Under  very 
large  quantities  the  neuromuscular  apparatus  appears  to  be  paralyzed  for 
adrenaline  causes  no  rise  in  pressure.  The  ganglia  on  the  course  of  the  auto- 
nomic nerves  are  also  weakened  or  paralyzed  by  these  alkaloids  in  large 
quantity. 

Some  diarrhoea  has  been  observed  after  the  administration  of  these  alkaloids, 
and  this  apparently  arises  from  accelerated  movement  of  the  intestine  (Cow). 
Diuresis  is  said  to  follow  their  use  in  some  instances. 

Some  authors  have  observed  a  change  in  the  red  corpuscles  under  quebrachine, 
but  its  nature  is  unknowai. 

Commercial  "  aspidospermine"  is  a  mixture  of  all  the  alkaloids  along  with 
other  bodies.     It  is  sometmies  prescribed  in  doses  of  1-2  mgs.  (^'u-gV  gr.). 

Aspidosperma  was  advised  by  Penzoldt  in  the  treatment  of  dyspnoea  from 
a  variety  of  causes,  and  his  statements  have  received  a  certain  amount  of 
support  from  clinicians.  The  special  conditions  in  wliich  it  has  been  advised 
are  dyspnoea  from  puhiionar}^  disease,  especially  emphj^sema,  and  from  car- 
diac weakness  and  asthma.  Its  action  on  the  respiratory  centre  may  explain 
to  some  extent  the  benefits  derived  from  it,  but  the  increased  secretion  of  the 
bronchi  produced  by  the  nausea  may  also  be  of  some  importance. 

Bibliography. 

HaTnack  u.  Hoffmann.     Zeitschr.  f.  klin.  Med.,  viii,  p.  471. 
Eloy  u.  Huchard.     Arch,  de  Phys.  [3],  vii,  1886,  p.  236. 
Guimann.     Arch.  f.  exp.  Path.  u.  Pharm.,  xiv.,  p.  451. 
Coiv.     Jour,  of  Pharmacology  v.,  p.  341. 

XXX.    QUININE. 

The  barks  of  various  species  of  Cinchona  and  Iiemijia  (Cuprea) 
contain  numerous  alkaloids  which  seem  to  resemble  each  other  closely 
in  their  chemical  and  pharmacological  properties.  The  best  known 
of  these  are  Quinine,  Quinidine,  or  Conquinine,  CincJionine  and  Cin- 
chonidine;  the  others,  amounting  to  some  twenty  in  number,  are 
believed  to  resemble  these  in  their  effects  on  the  organism,  but  very 
little  has  been  done  to  determine  this,  and  nothing  is  known  regarding 
their  relative  activity. 

The  cinchona  alkaloids  are  derivatives  of  quinoline.  Cinchonine 
and  cinchonidine  are  isomeric  (C19H22N2O)  and  perhaps  contain  two 
quinoline  molecules,  while  quinine  and  quinidine  (C20H24N2O2)  are 
methoxyl  compounds  of  cinchonine.^ 

Cinchona  bark  contains  besides  these  alkaloids  several  acids,  includ- 
ing tannins,  and  some  neutral  substances. 

'  The  other  alkaloids  of  this  series  which  have  been  identified  are  homocinchonidine, 
conquinamine,  quinamine,  cusconine,  concusconine,  aricine,  eusconidine,  cuscamine, 
cuscamidine,  hydroquinine,  hydroquinidine,  hydrocinchonine,  cinchonamine,  quaira- 
mine,  conquairamine,  quairamidine,  and  conquairamidine,  while  several  others  are  said 
to  have  been  separated  by  some  authorities,  but  are  rejected  by  others.  The  acids  gen- 
erally acknowledged  to  be  present  in  cinchona  are  quinic,  quinovic,  quinotannic,  quino- 
vatannic,  eaffeotannic  and  oxalic,  while  the  neutral  bitter  substances  have  been  named 
quiuDviu,  qiiinova-rod  and  cinchona-red. 


456  SUBSTANCES  ACTING  AFTER  ABSORPTION 

The  cinchonas  are  natives  of  Western  South  America,  but  are  now 
cultivated  in  India  and  Java.  It  seems  questionable  whether  the 
virtues  of  the  bark  were  known  by  the  native  Indians  before  the 
invasion  of  the  Spanish,  and  its  introduction  into  medicine  dates 
from  about  1630-1640;  its  name  bears  testimony  to  its  efficacy  in  the 
case  of  the  Countess  of  Chinchon  in  1638. 

Action. — Quinine  differs  from  most  of  the  other  important  alkaloids 
in  actiiiii;  not  on  some  specialized  form  of  li\  ing  matter,  but  on  the 
general  nutrition  of  almost  all  forms  of  pr<)t<)])lasm.  Other  alkaloids, 
such  as  strychnine,  are  also  possessed  of  similar  efl'ects  as  regards 
nutrition,  but  their  strong  affinity  for,  and  intense  action  on,  some 
special  tissue  prevent  their  effects  on  the  fundamental  ])roperties  of 
living  matter  from  being  elicited  in  the  higher  animals.  Quinine 
is  therefore  often  termed  a  protoplasm  poison  because  its  action 
extends  with  but  little  variation  throughout  most  forms  of  living 
matter.  The  effects  of  quinine  on  protojilasm  generally  consist  in 
transitory  augmentation  of  its  acti\ity,  followed  hy  depression  and  death. 

The  action  of  quinine  on  Undifferentiated  Protoplasm,  such  as  is 
found  in  the  unicellular  organisms  and  in  the  ovum,  is  therefore  of 
greater  interest  than  that  of  most  alkaloids.  Binz  found  that  while 
very  minute  quantities  sometimes  increase  the  movements  of  the 
amoeba  and  infusoria  at  first,  large  amounts  paralyze  them  imme- 
diately, and  the  protoplasm  assumes  a  darker  granular  appearance. 
The  rhythmic  movements  of  ciliated  organisms  are  rendered  slow  and 
finally  arrested  by  very  dilute  solutions,  but  no  other  organism  is  so 
susceptible  to  the  action  of  quinine  as  those  which  induce  malaria  in 
man.  The  microbes  of  putrefaction  are  also  acted  upon  by  quinine, 
although  they  are  more  resistant  than  the  protozoa;  still,  quinine 
solutions  have  considerable  antiseptic  power.  The  alcoholic,  lactic  and 
butyric  fermentations  are  retarded,  or  entirely  prevented  by  quinine 
through  its  effects  on  the  organisms,  but  it  is  apparently  devoid  of 
action  on  some  of  the  lower  forms,  for  moulds  (Penicillium)  grow 
freely  in  solutions  of  the  salts;  so  that  the  alkaloid  seems  to  ha\e  a 
selective  action  here,  such  as  is  observed  also  in  its  effects  on  the  fer- 
ments of  the  higher  animals.  Another  exam])le  of  its  action  on  the 
vegeta})le  cell  is  that  discovered  by  Darwin  in  some  insectivorous 
plants  (Drosera),  in  which  the  movements  seem  to  be  first  excited 
and  later  ])aralyzed  by  the  quinine  salts. 

The  infiuence  of  quinine  on  the  reproductive  cells  of  animals  has 
been  carefully  studied  by  ().  and  U.  Ilertwig,  who  found  that  both 
the  spermatozoon  and  the  ovum  of  the  sea-urchin  are  injured  by  the 
addition  of  quinine  to  the  sea-water,  the  movements  of  the  former 
being  i)aralyzed,  and  the  stages  ])receding  impregnation  in  tlu>  latter 
progressing  more  slowly,  or  actually  retroceding.  When  (|uiuine  is 
applied  after  the  male  nucleus  has  entered  the  o\um,  the  complete 
conjugation  is  delayed  and  the  whole  ])rocess  is  rendered  abnormal 
by  the  admission  of  several  spermatozoa.  Quinine  applied  still  later 
])revents  or  delays  the  division  of  the  o\  um  through  its  effects  both 
on  the  nucleus  and  on  the  general  protoplasm  of  the  ci'll. 


QUININE  457 

The  iiKli\i(lLuil  cells  of  more  complex  organisms  are  affected  in  the 
same  way  as  these  more  simple  ones.  This  was  first  demonstrated  in 
the  leucocytes  b\'  Binz,  and  after  some  opposition  has  been  generally 
accepted.  When  a  drop  of  blood  is  examined  under  the  microscope, 
the  white  cells  are  observed  undergoing  constant  changes  of  form  and 
position  exactly  similar  to  those  of  the  amoeba,  but  minute  quantities 
of  a  quinine  salt  are  sufficient  to  stop  all  movements  at  once,  and 
the  leucocytes  assume  a  spherical  form,  become  darker  in  color  and 
granular,  and  soon  break  up  into  debris.  In  the  blood\essels  similar 
changes  occur  when  quinine  is  applietl  locally,  as  to  the  frog's  meseii- 
tery;  the  leucocytes  again  become  darkly  granular,  and  ceasing  their 
creeping  movements,  are  carried  along  by  the  current  much  more 
rapidly  than  usual.  They  are  no  longer  observed  to  push  their  way 
through  the  vessel  walls,  and  if  they  have  already  penetrated  into  the 
tissues  their  movements  are  arrested.  If  irritation  be  applied  to  the 
part,  no  such  accumulation  of  leucocytes  occurs  in  the  tissues  as  in 
the  unpoisoned  animal,  and  if  an  irritant  has  been  applied  first  and 
the  leucocytes  have  poured  out  of  the  vessels  before  the  quinine  is 
applied,  the  process  is  arrested  at  once  on  its  application.  This  eft'ect 
was  explained  by  Binz  as  due  to  the  poison  acting  on  the  leucocytes, 
and  although  attempts  have  been  made  to  explain  it  by  some  change 
produced  on  the  vessel  wall  by  the  drug,  there  now  seems  no  reason 
to  question  the  correctness  of  his  view.  Similar  results  are  observed 
when  the  drug  is  not  applied  locally,  but  carried  to  the  part  by  the 
vessels;  the  movements  of  the  leucocytes  in  the  vessels  are  less  dis- 
tinct; they  are  carried  along  passively  in  the  general  current,  assume 
a  spherical  form,  and  have  much  less  tendency  to  escape  into  the  gen- 
eral tissues,  and  at  the  same  time  the  number  of  the  leucocytes  in  the 
blood  undergoes  a  considerable  diminution.  It  would  be  unjustifial3le 
to  infer  from  these  experiments  that  the  therapeutic  dose  of  quinine 
inhibits  the  movements  of  the  white-blood  cells-  in  the  human  body, 
and  it  is  no  part  of  Binz's  theory  that  this  occurs.  The  eft'ect  of 
quinine  on  the  leucocytes  is  merely  an  example  of  its  effects  on  the 
tissues  generally.  At  the  same  time  the  number  of  leucocytes  in  the 
human  blood  is  diminished  by  ordinary  quantities  of  quinine,  show- 
ing that  the  action  on  the  frog's  leucocytes  extends  also  to  those  of 
man,  even  when  the  quinine  is  absorbed  from  the  stomach  and  intestine. 

Other  evidence  of  the  action  of  quinine  is  gained  from  processes 
which  may  be  regarded  as  due  to  Unorganized  Ferments. 

Thus  the  oxidizing  action  of  drawn  blood  was  shown  to  be  dimin- 
ished in  several  experiments  performed  by  Binz.  For  example,  it 
fails  to  form  the  blue  oxidation  product  of  guaiac,  or  to  decolorize 
indigo  when  it  is  applied  to  it  along  with  quinine. ^    From  these  experi- 

1  The  well-known  guaiac  experiment  is  performed  as  follows:  A  fresh  solution  of 
guaiac  resin  in  alcohol,  to  which  some  peroxide  of  hydrogen  has  been  added,  is  divided 
into  two  parts.  To  the  one  a  minute  quantity  of  quinine  is  added,  and  one  or  two  drops 
of  blood  or  of  juice  from  a  living  plant  are  then  allowed  to  flow  into  each  part.  The 
one  containing  the  quinine  remains  uncolored,  while  the  other  assumes  a  blue  tint  from 
the  oxidation  of  the  guaiac  by  the  unpoisoned  blood. 


458  SUBSTANCES  ACTING  AFTER  ABSORPTION 

ments  the  inference  is  drawn  that  quinine  hinders  the  action  of  the 
oxidiziiij];  ferments  of  the  blood.  A  number  of  other  ferments  act  more 
xigorously  in  wry  dihite  sohitions  of  quinine,  while  they  are  retarded 
by  larger  quantities;  for  example,  the  autolytic  ferment  of  the  liver, 
pepsin,  and  rennet.  And  some  appear  to  be  much  less  susceptible  to 
its  action  than  others,  for  they  are  augmented  in  activity  by  quantities 
that  retard  or  destroy  those  more  readily  affected. 

These  experiments  indicate  that  quinine  hinders  some,  if  not  all,  of 
the  processes  which  normally  occur  in  living  matter,  and  which  are 
expressed  in  movement  and  in  various  chemical  products;  they  indi- 
cate in  addition  that  this  action  is  not  confined  to  the  intact  protoplasm, 
but  extends  to  some  of  the  ferments. 

Among  the  Vertebrates,  also,  small  quantities  of  quinine  gixe  rise 
to  disturbances  of  the  nutrition,  but  before  discussing  these,  it  may 
be  well  to  indicate  the  symptoms  induced  by  poisonous  doses. 

In  the  frog  a  short  stage  of  increased  reflex  excitability  is  followed  by  the 
loss  of  spontaneous  movements,  the  arrest  of  respiration  and  paralysis  of  the 
spinal  cord.  In  mammals  the  spinal  cord  is  said  to  be  stimulated  by  small 
quantities  and  then  to  be  depressed.  The  respiration  is  sometimes  accelerated 
in  the  beginning,  but  is  afterward  weakened,  and  its  failure  is  the  cause  of 
death.  General  depression  and  muscular  weakness  are  usually  the  only  cere- 
bral effects  noted,  and  the  tremor  and  convulsions  said  to  occur  in  some  in- 
stances may  be  due  to  the  use  of  impure  quinine.  The  heart  is  often  accelerated 
at  first,  but  is  afterward  slow  and  weak,  while  the  blood-pressure,  after  a 
slight  increase,  declines  progressively.  According  to  Santesson,  quinine  given 
by  the  stomach  has  comparatively  little  effect  on  the  heart  and  blood-pressure 
in  mammals.  These  symptoms  point  to  a  preliminary  stage  of  stimulation, 
followed  by  depression  of  the  Central  Nervous  System  and  heart  in  the  verte- 
brates, corresponding  to  the  two  stages  observed  in  the  simpler  organisms. 
They  are  only  elicited  by  very  large  quantities  of  .the  drug  and  have  perhaps 
received  greater  attention  than  they  merit  at  the  hands  of  experimental  phar- 
macologists. 

The  changes  in  the  Circulation  in  mammals  are  caused  by  a  preliminary 
contraction  of  the  arterioles  and  acceleration  of  the  heart,  followed  hy  dila- 
tion of  the  former  and  slowing  and  weakening  of  the  latter.  In  both  cases 
the  action  is  probably  a  direct  one  on  the  muscle  of  the  arterioles  and  heart, 
although  some  investigators  consider  the  acceleration  due  to  depression  of 
the  inhibitory  mechanism  in  the  heart  or  in  the  medulla  oblongata.  The 
effects  of  quinine  on  the  isolated  frog's  heart  have  been  studied  carefully  by 
Hantesson,  who  states  that  the  action  is  entirely  muscular  and  consists  in  slow- 
ing and  weakening  of  the  contractions.  In  fatal  poisoning  in  manunals  the 
lieart  is  generally  very  much  weakened  when  the  respiration  ceases,  but  con- 
tinues to  beat  for  some  time  afterward. 

Quinine  acts  upon  Muscle  in  the  same  way  as  upon  the  shni^lc  organisms, 
temijorarily  increasing  its  i)0wer  and  subsequently  weakening  it.  Thus  San- 
tesson found  that  the  strength  of  the  individual  contractions  was  increased 
and  that  a  contraction  occurred  against  greater  resistance  than  normally,  but 
when  the  stimulation  was  repeated,  fatigue  set  in  sooner  than  in  lll^  unpoisoned 
muscle.  Large  (luantities  of  (luinine  tln-ow  the  muscle  into  rigor,  which  re- 
sembles that  ])ro(lu('e(l  l)y  caffeine,  and  is  probably  associated  with  its  action 
in  accelerating  tlic  coagulation  of  myosin  (Furth). 

Tlie  Nerve  Trunks  arc  said  to  be  remarkal)ly  tolerant  to  solutions  of  ciuinine, 
wliicli  do  not  lessen  their  irritability  when  ajjplied  locally  in  sufiicient  (luantity 
to   cnusc   marked    abiiornialities   in    the   muscular  contraction.      Xo  sullicieiit 


QUININE  459 

evidence  has  been  brought  forward  that  (luinine  affects  the  peripheral  ends  of 
the  motor  or  sensory  nerves. 

A  sHght  increase  in  the  amount  of  Urine  excreted  lias  been  observed  some- 
times, but  docs  not  seem  constant.  It  is  attributed  to  the  action  of  the  quinine 
on  the  renal  epithelium,  l)y  which  it  is  excreted.  The  other  secretions  do  not 
seem  to  be  altered  by  quinine,  unless  it  is  applied  directly  to  the  cells  in  large 
quantity  bj^  injecting  solutions  into  the  duct  of  the  gland.  The  statement  is 
made  that  the  glycogenic  function  of  the  liver  is  altered  so  that  less  sugar  than 
usual  is  supplied  to  the  blood,  and  there  is  some  evidence  that  other  hepatic 
functions  are  less  active  than  usual. 

Cinchona  preparations  and  quinine  have  the  same  action  on  the 
appetite  and  digestion  in  man  as  the  simple  bitters  and  nux  vomica. 
Ordinary  therapeutic  doses  often  produce  no  very  obvious  symptoms, 
the  most  frequently  observed  effect  consisting  in  derangement  of  the 
Sense  of  Hearing,  less  frequently  of  that  of  Sight.  Ringing  or  roaring 
sounds  in  the  ears,  accompanied  by  slight  deafness,  are  produced  by 
moderate  quantities  and  large  doses  are  not  infrequently  followed  by 
complete  loss  of  hearing  for  a  time.  Contraction  of  the  field  of  vision 
is  observed  less  often,  but  in  some  cases  total  blindness  has  been  pro- 
duced and  has  lasted  for  several  days  or  even  -weeks.  Color-vision  is 
especially  liable  to  be  rendered  imperfect  or  temporarily  paralyzed  by 
quinine;  these  disorders  of  sight  are  accompanied  by  a  very  marked 
contraction  and  even  obliteration  of  the  retinal  vessels  and  sometimes 
by  degenerative  changes  in  the  retinal  nerve-cells  and  even  by  atrophy 
of  the  optic  nerve.  It  is  still  undecided  whether  the  vascular  changes 
or  the  nervous  degeneration  is  the  primary  lesion,  but  the  majority  of 
investigators  at  present  favor  the  view  that  the  constriction  of  the 
vessels  is  merely  an  accompaniment  of  the  graver  effects  on  the  gang- 
lionic structures.  The  symptoms  in  the  ear  have  generally  been  regarded 
as  the  result  of  congestion  and  haemorrhages  in  the  tympanum  and 
labyrinth,  but  Wittmaack  has  recently  shown  that  this  view  is  founded 
on  erroneous  observations,  and  states  that  degenerative  changes  occur 
in  the  spiral  ganglion  in  the  cochlea  exactly  analogous  to  those  de- 
scribed in  the  retina.  When  quinine  is  taken  continuously  as  a  prophy- 
lactic, it  is  said  to  impair  the  hearing  and  sight  permanently  in  some 
cases.  Quinine  possesses  some  irritant  action  which  betrays  itself  in 
discomfort  in  the  stomach  and  eructation  after  large  and  repeated  doses 
by  the  mouth,  and  by  pain  and  tenderness  when  it  is  injected  sub- 
cutaneously;  but  this  drawback  is  not  of  so  much  importance  as  in 
the  case  of  many  other  drugs. 

Large  doses  of  quinine  produce  some  confusion  and  depression  with 
a  sense  of  fulness  and  heaviness  in  the  head  from  their  action  on  the 
Cerebrum,  and  this  is  sometimes  accompanied  by  uncertain  gait  and 
slow  pulse.  Very  few  cases  of  fatal  poisoning  have  been  satisfac- 
torily determined  to  be  due  to  quinine,  although  a  considerably  larger 
number  ha^■e  been  attributed  to  it.  In  these  cases  marked  weakness 
of  the  heart  and  collapse  accompanied  by  loss  of  sight  and  hearing, 
muscular  weakness,  apathy,  slow,  gasping  respiration  and  finally 
unconsciousness   and   total   failure   of  the   respiration   were  observed. 


4G0  SUBSTANCES  ACTING  AFTER  ABSORPTION 

In  some  cases  delirium  and  convulsions  have  been  noted.  Enormous 
doses  of  quinine  sulphate  have  been  swallowed  without  any  serious 
results.  Thus  in  one  case  thirty  grammes  (one  ounce)  produced  only 
some  confusion  and  noises  in  the  ears. 

The  extensive  use  of  (juinine  in  tlierajieutics  has  demonstrated  that 
many  persons  have  curious  Idiosyncrasies  in  regard  to  it.  This  is 
betrayed  in  many  cases  by  the  development  of  ear  symptoms  after 
com])aratively  small  doses,  but  in  others  symptoms  arise  Avhich  do  not 
ai)poar  in  the  great  majority  of  people  even  after  large  doses.  The 
commonest  of  these  are  skin  eruptions,  of  whicii  a  large  variety  have 
been  described,  and  which  can  be  distinguished  from  ordinary  diseases 
of  the  skin  only  by  the  history  or  by  the  detection  of  quinine  in  the 
urine  or  in  the  stools.  These  exanthemata  are  often  accompanied 
by  some  rise  in  temperature,  which  has  received  more  attention  than 
it  ai)pears  to  deserve,  for  it  is  rare  and,  even  when  ])resent,  is  of  insig- 
nificant extent.  Other  less  important  effects,  whicli  have  l^een  occa- 
sionally noted,  are  gastric  discomfort  and  diarrhoea.  In  some  cases  the 
administration  of  quinine  is  followed  by  fever  and  hi\^moglobinuria 
(black  water)  or  albuminuria.  The  exact  relation  between  quinine  and 
this  condition  is  a  matter  of  dispute;  blackwater  fever  occurs  in  sufferers 
from  old  malarial  infection  occasionally  when  no  quinine  has  been 
given,  but  in  many  cases  the  symptom  is  provoked  only  by  quinine; 
on  the  other  hand  it  often  passes  off  when  the  treatment  is 
continued.  Quinine  has  no  hemolytic  action  except  in  quantities 
which  would  prove  immediately  fatal,  and  the  blood  of  these  black- 
water  i)atients  is  not  more  readily  laked  by  it  than  normal  blood. 

The  Uterus  is  aroused  to  contraction  by  quinine,  and  abortion  occurs 
occasionally  after  its  use  in  malaria,  while  in  other  cases  labor  pains 
may  be  induced.  Many  physicians  use  it  during  labor  if  the  pains 
cease  or  if  they  seem  to  be  too  weak  to  expel  the  child.  In  animal 
ex])eriments  it  is  found  that  quinine  injected  intravenously  or  hypo- 
derniically  causes  rhythmical  contractions  of  the  uterus  or  strengthens 
the  spontaneous  contractions  when  these  are  present.  The  tone  of 
the  muscle  is  also  augmented.  The  action  appears  to  be  a  direct  one 
on  the  uterine  muscle  and  may  be  observed  in  the  excised  organ. 

In  the  Alimentary  Tract  quinine  and  the  cinchona  preparations  act  in  the 
same  way  as  the  simple  bitters  (page  51 ).  It  is  said  to  lessen  the  secretion 
of  the  gastric  jnice  in  the  dog  for  some  days  after  a  single  administration. 

The  Blood  generally  contains  fewer  leucocytes  after  quinine  in  man 
and  in  animals.  According  to  Roth  a  single  dose  generally  causes 
leucocytosis  at  first,  j^robably  arising  from  contraction  of  the  spleen, 
'i'liis  is  followed  by  a  fall  in  the  number  of  white  corpuscles,  esi)eciall\- 
of  the  lymj)hocytes,  though  the  i)()lynuclear  cells  are  also  reduced. 
The  pol\nuclears  then  increase  in  number  until  a  distinct  leucocytosis 
is  again  present,  but  the  lymphocytes  remain  reduced  in  number  while 
in  the  prcliniinar\'  leucocytosis  they  predominate. 

Tlic  Spleen  undergoes  a  marked  diniiiuition  in  size  (Roth),  presumably 
from  actixc  contraction  of  its  nuiscnlar  fibres.  A  similar  constriction 
lias  been  obscrxcd  in  tlic  bronchi  in  animals. 


QUININE  461 

The  constant  cllects  of  (|uinine  on  the  Metabolism,  wliicli  arc  pro- 
duced by  quantities  of  the  drug  too  small  to  have  any  further  action 
except  in  specially  susceptible  individuals,  are  of  much  greater  inter- 
est and  importance  than  the  symptoms  already  mentioned.  This 
alteration  of  the  tissue  change  occurs  throughout  the  mammalia,  and 
consists  in  a  marked  diminution  in  the  destruction  of  the  nitrogenous 
constituents  of  the  tissues.  After  the  administration  of  quinine,  the 
nitrogen  in  the  urine  is  found  at  first  slightly  augmented  for  a  few 
hours,  but  then  undergoes  a  diminution  of  considerable  extent,  due 
to  a  restricted  production  of  all  the  nitrogenous  constituents  of  the 
urine,  but  especially  of  the  urea  and  uric  acid.  The  phosphates  and 
sulphates  undergo  a  corresponding  alteration,  but  all  metabolic  changes 
are  not  affected,  for  the  carbonic  acid  exhaled  and  the  oxygen  absorbed 
by  the  lungs  present  no  marked  alteration  in  amount,  so  that  the 
oxidation  of  the  tissues  cannot  be  said  to  be  altered,  but  only  the 
breaking  doAvn  of  the  nitrogenous  bodies.  This  absence  of  effect  on  the 
oxidation  of  the  body  is  not  what  might  have  been  expected  from  the 
experiments  of  Binz  and  others  on  the  simpler  tissues,  for  these 
showed  that  oxidation  of  all  kinds  was  retarded  by  quinine.  On  the 
other  hand,  it  corresponds  with  Jacquet's  obser^'ation  that  quinine 
does  not  retard  the  oxidation  of  substances  perfused  through  excised 
organs,  and  has  been  attested  by  many  observers.  In  the  case  of  several 
other  drugs  the  diminution  of  the  urea  is  compensated  for  by  the 
increase  in  the  other  nitrogenous  bodies  in  the  urine,  but  the  fall  in 
the  total  excretion  of  nitrogen  after  quinine  points  to  an  alteration 
of  the  metabolism  of  the  body  in  general,  and  not  to  the  paralysis  or 
destruction  of  the  organs  which  change  the  first  products  of  the 
nitrogenous  metabolism  to  the  simpler  forms  in  which  they  are  finally 
excreted.  The  oxygen  absorbed  and  the  carbonic  acid  excreted  by 
the  tissues  are  generally  held  to  measure  the  amount  of  work  done 
and  heat  formed  by  the  muscular  and  other  activities  of  the  body, 
and  quinine  therefore  does  not  seem  to  affect  these  functions,  while  it 
would  appear  that  some  other  processes,  perhaps  the  death,  growth, 
and  repair  of  the  tissues,  are  less  active  than  normally.  At  any  rate, 
the  nitrogenous  food  is  not  dissipated  so  rapidly,  but  is  stored  up  in 
the  body  in  some  unknown  form,  for  v.  Noorden  found  that  under 
constant  diet  the  nitrogen  excretion  diminished  under  quinine,  and 
this  diminution  continued  for  two  days  after  the  treatment  was 
stopped.  The  nitrogen  absorbed  from  the  alimentary  canal  remained 
unchanged,  and  a  certain  amount  of  protein  food  must  therefore  have 
been  added  to  the  body  and  saved  from  the  decomposition  which  it 
would  have  undergone  in  ordinary  circumstances. 

Temperature. — The  specific  action  of  quinine  in  preventing  the  par- 
oxysms of  fe\er  in  malaria  soon  led  to  its  use  in  other  forms  of  fever, 
and  it  has  generally  been  held  that  quinine  has  a  specific  action  in  re- 
ducing fcA'er  tem})erature.  As  a  matter  of  fact  the  temperature  is  not 
reduced  in  malaria  by  action  on  the  tissues,  but  by  destruction  of  the 
parasite  which  causes  the  rise  in  temperature;  and  until  this  is  accom- 


4ry2  SUBSTANCES  ACTlSd  AFTER  ABSORPTIOS 

plished,  (|uiiiiiie  is  unable  to  reduce  the  body  lieat  or  e\en  to  ))re\ciit 
its  rising.  In  other  forms  of  fever,  ciuinine  not  infre(iuently  fails  to 
reduce  the  temperature  in  man.  In  animals  large  doses  are  found  to 
lower  fever  temperature,  but  this  is  often  accompanied  by  such  symp- 
toms as  depression  and  muscular  weakness,  \\\\\c\\  in  themselves  would 
reduce  the  amount  of  heat  formed  and  thus  lower  the  unstable  fever 
tem])erature.  In  health,  quinine  has  no  effect  on  the  tem])erature  as  a 
general  rule;  in  some  cases  a  very  slight  fall,  in  others  an  equally  in- 
significant rise  in  the  thermometer  follows  its  administration. 

This  antipyretic  action  of  quinine  has  been  the  subject  of  a  number 
of  in^•estigations,  which  have  given  varying  results.  The  general 
view  is  that  in  fever  quinine  reduces  the  heat  production  l)y  the  changes 
which  it  effects  in  the  general  metabolism;  these  are  not  due  to  any 
central  nervous  action  but  are  rather  to  be  regarded  as  analogous 
to  the  action  on  the  simpler  organisms  and  the  ferments.  But  the  only 
change  of  this  character  that  is  known  is  the  reduced  nitrogenous 
excretion;  and  heat  formation  is  believed  to  be  associated  exclusively 
with  the  oxidation  of  carbon  and  hydrogen,  which  has  not  been  shown 
to  be  altered  by  quinine.  On  the  contrary,  repeated  investigations  have 
shown  that  the  carbonic  acid  eliminated  is  not  materially  altered  by 
quinine;  but  the  changes  in  cases  Avhere  quinine  lowers  the  temperature 
have  not  been  sufficiently  controlled.  The  further  statement  is  made 
that  when  normal  animals  under  quinine  are  exposed  to  heat,  their 
temperature  does  not  rise  to  the  same  extent  as  that  of  untreated 
controls,  and  this  is  attributed  to  their  metabolism  being  less  rapid. 

The  reduction  in  heat  formation  is  accompanied  by  an  augmented 
heat  loss  in  some  cases,  while  in  others  the  output  remains  unchanged 
or  may  be  diminished.  This  change  in  the  output  of  heat  indicates 
activity  of  the  heat  regulating  ai)i)aratus  of  the  brain,  but  most  investi- 
gators hold  that  the  temperature  may  fall  under  quinine  when  this 
centre  is  put  out  of  activity  by  section  of  the  spinal  cord.  In  many  of 
the  experiments  on  animals  it  appears  that  the  possible  action  of  large 
doses  of  quinine  on  the  central  nervous  system  and  circulation  have  not 
been  taken  into  account  sufficiently,  and  that  some  of  tlie  results 
which  have  been  attributed  to  metabolic  changes  may  have  arisen 
from  changes  in  these  systems. 

In  spite  of  these  difficulties,  quinine  is  generally  held  to  reduce  the 
temperature  in  fever  by  lessening  the  metabolism  in  the  tissues  i)y  a 
direct  action  on  the  individual  cells.  The  subject  requires  further 
examination,  which  might  well  begin  by  a  satisfactory  determination  of 
what  forms  of  fever  shoAv  significant  remissions  under  treatment  with 
fiuinine.  It  is  quite  possible  that  it  will  then  emerge  that  the  action  on 
the  tcnipcraturc  is  indirect,  as  in  the  case  of  malaria;  the  temperature 
may  fall  l)ecause  the  cause  of  the  fever  is  abated  by  (luiuine.  or  because 
the  tissues  offer  greater  resistance  to  the  virus  and  thus  fewer  poisonous 
products  arc  thrown  into  the  ch-culation. 

Excretion.  (Quinine  appears  in  the  urine  within  a  short  time  ( b") 
ininntes)  after  its  exhibition  by  the  mouth,  and  it  continues  to  be 
excreted  by  the  kidney  in  some  quantity  during  the  next  twenty-four 


QUININE  4G3 

hours,  and  in  smaller  amounts  up  tt)  about  seventy-two  hours.  Only 
about  one-third  of  that  absorbed  appears  in  the  urine,  however,  and 
none  whatever  has  been  found  in  the  other  excretions,  so  that  from 
two-thirds  to  three-fourths  undergoes  complete  destruction  in  the  tis- 
sues. In  the  dog  a  smaller  proportion  is  excreted  in  the  urine,  but 
otherwise  the  drug  is  eliminated  in  the  same  way  and  in  the  same 
unchanged  form  as  in  man.  Rather  less  seems  to  be  excreted  when  the 
quinine  is  injected  hypodermically  than  when  it  is  taken  by  the  mouth. 
Quinine  is  found  only  in  traces  in  the  blood  and  organs,  and  it  has 
not  been  found  to  accumulate  in  any  part  of  the  body. 

Of  the  Other  Cinchona  Alkaloids,  quinidine  or  conquinine  resembles  quinine 
most  closely  in  its  effects,  which  are  somewhat  weaker,  however.  Cinchonine, 
while  very  similar  to  quinine  in  most  points,  has  some  tendency  to  produce 
convulsions,  but  this  effect  is  nmch  more  liable  to  occur  under  chichonidine, 
which,  save  for  its  resemblance  in  other  features  to  quinine,  would  be  entitled 
to  be  classed  among  the  convulsive  poisons.  These  convulsions  are  of  an 
epileptiform  character,  and  are  only  produced  by  very  large  doses,  but  Albertoni 
discovered  that  even  small  quantities  administered  to  epileptics  increased  the 
number  of  the  attacks.  He  found  that  these  epileptiform  seizures  were  not 
prevented  bj^  the  removal  of  the  cerebral  cortex  in  dogs,  and  that  the  irritability 
of  the  motor  areas  was  not  altered  by  cinchonidine,  and  therefore  concluded 
that  the  poison  produced  these  symptoms  by  acting  on  some  lower  division 
of  the  central  nervous  axis.  It  is  possible  that  this  is  true  for  the  lower 
animals  but  that  in  man  the  more  highly  developed  cerebral  cortex  is  also 
involved. 

In  other  respects  cinchonine  and  cinchonidine  differ  from  quinine  only  in 
the  degree  and  not  in  the  kind  of  their  action.  Cinchonamine  possesses  an  even 
more  marked  convulsant  action  than  cinchonidine. 

The  effects  of  the  other  alkaloids  have  not  been  the  subject  of  much  investi- 
gation, but  they  seem  to  differ  from  quinine  chiefly  in  their  effects  on  the  central 
nervous  system.  These  are  not  entirely  absent  in  quinine  itself,  for,  as  has  been 
stated  already,  the  reflex  irritability  is  at  first  increased  and  then  diminished 
in  both  frogs  and  mammals,  and  in  some  cases  even  convulsions  are  stated 
to  have  occurred  in  quinine  poisoning. 

Cinchonidine  is  the  most  poisonous  of  the  four  chief  alkaloids,  quinine  follow- 
ing next,  and  then  cinchonine  and  quinidine. 

Preparations. 

U.  S.  P. — Cinchona,  the  bark  of  Cinchona  Ledgeriana,  C.  calisaya  and  C. 
officinalis  and  of  hybrids  of  these  and  of  other  species  of  Cinchona,  yielding 
not  less  than  5  per  cent,  of  total  alkaloids.    Dose,  1  G.  (15  grs.). 

Cinchona  Rubra,  red  cinchona,  the  bark  of  Cinchona  succirubra,  containing 
at  least  5  per  cent,  of  alkaloids.    Dose,  1  G.  (15  grs.). 

Fluidexiractmn  Cinchona;  contains  4  per  cent,  of  quinine,  quinidine  and 
cinchonidine,  1  c.c.  (15  mins.). 

TiNCTURA  Cinchona  contains  0.75  per  cent,  of  these  alkaloids,  4  c.c.  (1  fl.  dr.). 

TiNCTURA  Cinchona  Composita  is  the  only  preparation  of  red  cinchona, 
and  contains  in  addition  serpcntaria  and  bitter  orange  peel.    4  c.c.  (1  fl.  dr.). 

QUININA, 


QuiNiN-E  Sulphas, 
QuinmcB  Bisulphas, 
Q  uiyiin  oe  Hydrobromidum , 
QuiNiNyB  Hydrochloridum 
Cinchonina'  Sulphas 


0.25  G.  (4  grs.). 


Cinchonidinoi  Sidphas, 


0.25  G.  (4  grs.). 


464  SUBSTANCES  ACTING  AFTER  ABSORPTION 

B.  P. — Cinchonse  Rubrae  Cortex,  red  cinchona  bark,  the  dried  bark  of  the 
stem  and  l)ranches  of  Cinchona  succirubra.  It  ought  to  contain  5-6  per  cent, 
of  total  alkaloids,  of  which  one  half  should  consist  of  quinine  and  cinchonidine. 

TixcTURA  CiN'CHON.E,  1  per  cent,  of  alkaloids,  ^-1  fl.  dr. 

TixcTURA  CiNCHOx.B  CoMPOSiTA,  Containing  bitter  orange  peel,  serpentary 
and  coloring  matters,  ^1  fl.  dr. 

Infnsum  Cinchonx  Acidum,  containing  aromatic  sulphuric  acid,  ^-1  fl.  oz. 

QuixiN.E  Hydrochloridum,  ] 

Quinince  Hydrochloridum  Acidum,       )■  1-10  grs. 

QuixiN.E  Sulphas,  J 

Tindura  Qxdnince  Ammoniata,  formed  from  the  sulphate,  |-1  fl.  dr. 

The  preparations  of  cinchona  were  formerly  much  more  in  vogue  than  at 
the  present  da}',  in  which  they  have  been  replaced  for  most  purposes  by  the 
alkaloids.  Thej'  are  still  prescribed  alone  or  together  with  other  remedies  as 
stomachic  bitters. 

Quinine  is"  practically  insoluble  in  water  and  several  of  its  salts  are  only 
dissolved  sparingh'.  Thus,  the  sulphate  requires  800  times  its  o-mi  weight  of 
water,  the  hydrochloride  35,  and  the  hydrobromide  40.  The  presence  of  acid 
in  excess  renders  them  much  more  soluble,  and  the  acid  hj-drochloride  is  dis- 
solved in  less  than  its  o-rti  weight  of  water,  the  bisulphate  in  10  parts.  They 
all  form  crystalline  powders  with  a  very  bitter  taste,  and  their  solutions  in  water 
have  a  blue  fluorescence  when  sulphuric  acid  is  present.  The  acid  hj'dro- 
cliloride  and  the  bisulphate  have  an  acid  reaction,  the  others  are  neutral. 

The  hydrochloride  of  quinine  is  the  most  soluble  of  the  salts  and  is  therefore 
preferable  to  the  others;  the  sulphate  is  frequently  prescribed,  the  hydrobromide 
comparatively  seldom.  Instead  of  the  acid  salts  being  prescribed,  some  sul- 
phuric acid  or  hydrochloric  acid  may  be  ordered  to  be  added  to  the  neutral  salts 
in  order  to  facilitate  their  solution. 

The  salts  of  quinine  are  frequently  given  in  the  form  of  piUs,  cachets,  tablets, 
or  capsules,  wliich  have  the  advantage  of  avoiding  the  bitter  taste,  but  from 
which  the  alkaloid  is  more  slowly  absorbed  than  from  solutions.  Care  must 
be  taken  that  the  pills  are  soft  and  freshly  prepared,  as  when  kept  for  any 
length  of  time  they  become  hard,  and  in  this  condition  frequently  pass  through 
the  bowel  unabsorbed.  The  salts  or  the  pure  alkaloid  maj'  also  be  given  as 
powders,  or  the  former  in  solution,  but  these  are  objected  to  bj^  many  patients 
on  account  of  the  bitter  taste.  When  rapid  absorption  is  desired,  solutions 
should  be  used,  flavored,  if  necessary,  with  s^Tup  and  volatile  oils.  Solutions 
of  the  salts  are  occasionally'  injected  as  enemata,  but  are  liable  to  set  up  irrita- 
tion and  to  be  rapidly  evacuated.  The  hypodermic  method  has  also  been  advised 
in  cases  of  emergency,  or  where  the  salt  cannot  be  retamed  or  absorbed  from  the 
stomach;  for  this  purpose  a  solution  of  the  hydrochloride  with  hydrochloric  acid 
in  excess  or  of  the  bisulphate  is  injected  deeply  into  the  muscular  tissue.  This 
form  of  medication  is  painful,  but  does  not  seem  to  induce  more  serious  results 
if  ordinary  care  is  used.  The  neutral  hydrochloride  may  be  dissolved  in  hot 
water  and  injected  when  the  solution  reaches  the  bodj'  temperature  \nth  less 
pain  than  is  elicited  by  other  salts.  In  this  way  about  two  parts  of  water  arc 
required  to  dissolve  one  of  quinine.  Quinine  is  verj'  easily  dissolved  in  water 
when  it  is  mixed  with  antipjTine  or  urea  in  the  proportion  of  three  parts  of 
quinine  to  two,  and  this  solution  is  less  painful  when  it  is  injected  hj'podermic- 
ally  than  others  owing  to  a  local  anaesthetizing  action  of  the  compound.  A 
hydrochloride  of  quinine  and  urea  containing  60  per  cent,  of  quinine  has  been 
largely  used  in  somewhat  larger  doses  than  those  of  quinine.  The  intravenous 
injection  of  ciuinine  has  been  practised  with  success  in  cases  of  pernicious 
malaria;  the  hydrochloride  dissolved  in  a  solution  of  conunon  salt  is  injected 
into  one  of  the  veins  of  the  arm. 

Many  other  salts  of  quinine  have  been  proposed  and  have  enjoj'ed  a 
certain  reputation  for  some  time.  Among  the  better  known  of  these  is  the 
tnnnote,  which  is  exceedingly  insoluble  and  has  less  taste,  and  is  prescribed 
in  powder  in  doses  of  1-3  G.     Other  salts  which  have  been  recommended 


QUININE  10.') 

are  the  tartrate  and  the  lactate.  Euquinine  is  the  very  insoluble  ethyl-ester 
of  quinine-carbonic  acid  (CO(OC2H5)(OC2oH23X20)  )  and  possesses  the  thera- 
peutic virtues  of  quinine  with  a  less  bitter  taste  and  without  inducing  ring- 
ing in  the  ears  and  other  S3'mptoms.  Aristochine  (CO(C2oH23N20)2)  and  Clun- 
aphenine  (CO(XH.C6H4.0C2H5)(OC2oH23X20)  )  are  less  satisfactory  compounds 
of  quinine  of  a  similar  nature.  AH  three  preparations  are  prescribed  in  powder 
or  tablets,  in  the  same  dose  as  quinine. 

A  famous  preparation  of  quinine  is  Warburg's  tincture,  which  has  been  exten- 
sively used  in  India  in  the  treatment  of  malaria.  It  contained  a  very  large 
number  of  ingredients,  mam'  of  wlaich  were  certainly  entirely  superfluous. 
Among  the  more  important  constituents  were  aloes,  rhubarb,  gentian,  camphor, 
and  various  volatile  oils;  it  is  possible  that  some  of  these  may  have  aided  the 
quinine  through  their  effects  on  the  stomach.  Various  drugs,  such  as  capsicum 
and  piperine,  have  long  had  some  reputation  as  adjuvants  in  quinine  treatment 
for  a  similar  reason. 

The  other  alkaloids  have  been  used  occasionally  as  substitutes  for  quinine, 
but  have  somewhat  less  therapeutic  effect,  while  cinchonidine  is  more  liable  to 
produce  s^inptoms  of  poisoning.  They  might  all  be  dispensed  with,  witliout 
loss  to  therapeutics. 

Therapeutic  Uses. — The  introduction  of  cinchona  into  therapeutics 
was  due  to  the  discovery  of  its  efficacy  in  ague  or  Malaria,  and  with 
growing  experience  in  the  disease  and  its  treatment,  the  confidence  in 
the  drug,  or  rather  in  its  chief  alkaloid,  has  constantly  increased,  until 
the  action  of  ciuinine  in  malaria  is  now  quoted  as  the  best  example  of 
a  specific  in  therapeutics.  The  explanation  of  its  action  has  only 
been  arrived  at  within  the  last  few  years  with  the  discovery  of  the 
parasites  of  malaria,  although  in  1S68  Binz  suggested  that  the  then 
unknown  malarial  poison  was  probably  rendered  inert  by  quinine. 
Malaria  is  now  known  to  be  due  to  three  distinct  parasites,  which  harbor 
in  the  red-blood  corpuscles  and  multipl}'  there,  and  then  issuing  from  the 
cells  in  immense  numbers  invade  new  corpuscles.  When  the  spores 
break  out  of  the  red  cells,  there  is  a  sharp  attack  of  fever,  which  passes 
off  when  they  have  reached  the  interior  of  new  corpuscles,  but  returns 
when  a  new  swarm  of  spores  is  liberated.  The  fever  thus  recurs  at 
regular  inter\als  in  the  simpler  forms  of  malaria,  but  may  be  rendered 
irregular  bj^  double  or  multiple  infections.  The  parasites  of  malaria 
belong  to  the  group  of  the  protozoa  and  are  thus  nearly  related  to  the 
amoeba  on  which  Binz  made  his  observations,  and  also  to  the  organism 
of  amoebic  dysentery  and  of  syphilis. 

The  organisms  of  malaria  are  most  susceptible  to  quinine  when  they 
are  in  the  free  state  in  the  plasma,  though  the  less  dangerous  forms  are 
also  destroyed  after  they  have  reached  the  shelter  of  the  corpuscles. 
In  the  more  malignant  form  of  infection,  the  parasites  in  the  cor])iiscles 
are  apparently  not  affected  by  quinine  and  can  only  be  got  rid  of  by 
preventing  them  from  being  reinforced  by  new  broods.  It  is  therefore 
of  the  first  importance  to  supply  quinine  to  the  blood  at  the  period  at 
which  the  spores  are  liberated.  When  quinine  is  given  at  the  appropriate 
time,  the  organism  breaks  up  and  disapjiears,  but  a  few  more  resistant 
forms  may  escape  and  multiply  until  they  aie  numerous  enough  to 
provoke  another  paroxysm  of  fever;  the  treatm  nt  is  therefore  continued 
until  all  the  parasites  have  succumbed. 
30 


4GG 


SUBSTANCES  ACTING  AFTER  ABSORPTION 


In  a  droj)  of  malarial  blood  the  plasniodia  may  be  seen  in  active 
movement,  bnt  a  minute  drop  of  quinine  solution  i)aralyzes  and  kills 
them,  exactly  as  it  kills  the  amoeba.  The  malarial  organisms  are  much 
more  susceptible  to  quinine  than  the  common  water  amoeba,  however; 
another  organism  which  is  found  in  the  blood  of  birds  has  proved 
resistant  to  quinine.  The  explanation  of  the  action  of  quinine  on  malaria 
lies  in  its  efi'ects  as  a  protoplasmic  poison,  therefore,  which  acts  more 
strongly  (specifically)  on  the  protozoa  wliich  are  the  cause  of  ague, 
and  can  consequently  be  introduced  into  the  human  body  with  impunity 
in  doses  which  are  destructive  to  the  simpler  organisms  which  have 
invaded  it.  Experience  has  shown  that  quinine  is  most  effective  when 
it  can  act  during  and  immediately  after  the  paroxysms,  and  this  is 

Fig.  63 


■ 

HOURS 

3 

B 

9 

12 

15 

18 

21 

24 

3 

6 

9 

12 

IS 

18 

21 

24 

3 

C 

9 

12 

15 

18 

21 

24 

3 

G 

9 

12 

16 

18 

21 

24 

- 

105° 

lOi" 

1 

103° 

I 

\ 

z; 

X102" 

— 

g  101° 

H 

^100° 

/ 

— 

f 

i 

h- 

99° 

^  \   1  \  r 

- 

- 

k  A  /  A/ 

V 

98° 

r 

\ 

\l 

97° 

I 

V 

Temperature  chart  in  a  cafee  of  malaria  in  which  quinine  (10  prains)  was  adminis- 
tered in  the  third  paroxysm  as  the  temperature  was  falling.  On  the  following  day  no  rise 
of  temperature  occurs.    The  temperature  was  taken  every  three  hours.     (Dock.)' 


now  explained  by  the  fact  that  the  organisms  are  in  their  least  resistant 
form  -the  amcrboid — at  this  time.  If  quinine  is  given  three  or  four 
hours  before  an  attack,  sufKcient  will  remain  in  the  blotxl  when  the 
temj)erature  begins  to  fall  to  destroy  the  unprotected  spores  of  the 
parasite,  or  the  same  result  may  be  obtained  by  a  dose  given  as  the 
temperature  begins  to  fall,  provided  the  drug  is  rapidly  absorbed,  as  is 
ordinarily  the  case.  It  may  be  ordered  in  one  dose  of  about  1  (t.  (15 
grs.),  or  in  divided  (:K)ses  given  at  intervals  during  the  fall  of  the  tem- 
perature. This  frequently  prevents  the  next  attack,  but  the  treatment 
should  be  continued  for  a  month,  beginning  Avith  five  grains  three  times 
a  day  and  gradually  reducing  the  dose  to  three  grains.  In  the  se\erer 
forms  of  infection  larger  d()S(>s  are  necessar\-,  and  fi\e  grains  ever\'  four 


QUININE  4G7 

hours  may  be  necessary  during  tlie  first  week,  followed  by  2-3-grain 
doses  three  times  a  day  for  a  month;  if  relapses  occur,  the  dose  must  be 
increased  again.  Some  authorities  recommended  that  instead  of  this 
continuous  administration,  single  large  doses  (15  grs.)  should  be  given 
at  intervals  so  timed  as  to  supply  the  drug  at  the  moment  of  sporula- 
tion,  but  this  is  not  so  generally  successful  as  the  continuous  treatment. 

Quinine  is  generally  administered  by  the  mouth  in  malaria,  but  its 
intensely  bitter  taste  renders  this  treatment  disagreeable,  and  in  chil- 
dren and  in  cases  of  persistent  vomiting  it  may  be  impossible;  in 
children  quinine  tannate  or  euquinine  may  be  employed,  and  in  severe 
vomiting  or  other  emergencies  a  soluble  preparation  is  injected  into  the 
muscles.  This  injection  is  often  painful,  but  causes  no  serious  injury 
such  as  may  follow  injection  into  the  subcutaneous  tissue,  in  which 
sloughing  has  sometimes  been  caused.  In  malignant  malaria,  quinine 
is  best  gi^'en  intravenously  in  fifteen-grain  doses  repeated  if  necessary 
after  six  hours;  for  this  purpose  the  hydrochloride  dissolved  in  warm 
saline  is  the  best  preparation,  the  more  soluble  acid  salts  tending  to 
react  with  the  blood  proteins.  A  great  deal  of  weight  was  formerly  laid 
on  the  use  of  purgatives  and  emetics  as  preliminaries  to  the  treat- 
ment of  malaria  with  quinine,  and  the  former  are  undoubtedly  of 
service  sometimes,  although  it  is  unnecessary  to  delay  the  quinine 
treatment  by  waiting  for  the  intestines  to  be  evacuated. 

Quinine  is  used  not  only  as  a  remedy,  but  also  as  a  prophylactic 
against  malaria.  Its  value  for  this  purpose  has  been  attested  by  long 
experience,  but  there  is  still  no  unanimity  of  opinion  as  to  the  best 
method  of  administration  and  the  dose  required.  Thus  Koch  advised 
15  grs.  to  be  taken  on  two  consecutive  days  every  week  or  ten  days, 
others  suggest  8  grs.  every  fourth  day,  while  a  common  prophylactic 
treatment  is  to  take  3-5  grs.  daily  and  10  grs.  once  a  week.  Quinine 
is  best  taken  after  meals,  when  it  disturbs  the  digestion  least.^ 

One  of  the  results  of  quinine  medication  in  early  cases  of  malaria 
is  the  reduction  of  the  enlarged  spleen,  and  this  has  led  to  its  use  in 
other  Diseases  of  the  Spleen  with  enlargement.  In  malaria  the  effect 
on  the  spleen  is  only  secondary  to  the  removal  of  the  cause  of  the  dis- 
ease, but  the  action  of  quinine  in  lessening  the  ninnber  of  leucocytes 
in  the  blood  and  in  contracting  the  muscle  fibres  of  the  spleen  may 
explain  its  being  of  benefit  in  other  splenic  disorders.  In  some  cases  of 
leuccemic  enlargement  encouraging  results  have  been  obtained  from  the 
continued  use  of  quinine. 

Various  other  Febrile  Conditions  ha\'e  been  treated  with  quinine, 
partly  for  the  sake  of  its  antipyretic  effects  and  partly  in  the  belief 
that  it  acts  as  an  antiseptic  in  the  blood.  As  regards  its  effect  on  the 
temperature  in  non-malarial  fever,  it  not  infrequently  causes  a  con- 
siderable fall,  and  has  the  advantage  of  possessing  a  more  prolonged 

'  Several  other  alkaloids  were  formerly  suggested  as  substitutes  for  quinine  in  malaria; 
thus  berberine  and  buxine  had  formerly  some  reputation,  and  harmine  (from  Peganum 
Harmala)  has  recently  been  subjected  to  trial,  but  none  of  these  has  proved  to  possess 
the  parasiticide  power  of  quinine,  although  they  all  have  some  effect  in  the  disease. 


4()S  SUBSTANCES  ACTING  AFTER  ABSORl'TION 

action  and  of  causing  less  risk  of  depression  and  collapse  than  the 
newer  antipyretics.  On  the  other  hand,  the  fev^er  is  not  reduced  so 
ra])i(ll\'  and  generally  not  to  the  same  extent  as  by  the  latter,  and  the 
large  ([uantities  of  quinine  reciuired  are  liable  to  cause  discomfort 
from  their  effects  on  the  brain  and  hearing.  ""J'^phoid  fever,  scarla- 
tina, pneumonia,  and  other  acute  pyrexias  are  sometimes  treated  with 
([uinine  for  this  effect.  The  best  results  are  obtained  when  it  is  exhibited 
in  maximal  doses  when  the  temperature  is  falling  or  when  it  has  been 
temj)orarily  reduced  by  other  means,  such  as  cold  baths.  Perhai)s, 
however,  the  beneficial  action  of  quinine  in  those  cases  ought  to  be 
measured  not  so  much  by  the  reduction  of  the  body  temperature  as  by 
the  lessened  destruction  of  the  tissues.  In  general,  antipyrine  and  its 
allies  have  succeeded  in  ousting  quinine  from  its  former  position  as 
the  best  of  the  antipyretics.  The  use  of  quinine  has  been  recom- 
mended in  septicaemia,  largely  from  a  belief  in  its  antiseptic  action 
in  the  blood.  In  this  connection  it  is  to  be  remarked  that  the  microbes 
of  septic  fever  are  very  much  more  resistant  to  the  action  of  quinine 
outside  the  body  than  are  the  protozoa,  and  the  question  therefore 
arises  whether  the  blood  and  tissues  are  not  liable  to  be  seriously 
injured  by  the  quantity  of  quinine  required  to  act  on  the  parasites 
they  contain.  In  many  cases  of  septicemia  in  which  beneficial 
results  are  said  to  have  been  obtained  by  the  use  of  quinine,  the  (juan- 
tity  administered  was  obviously  too  small  to  have  any  effect  either 
on  the  temperature  or  on  the  microbes.^ 

Quinine  has  been  used  in  various  forms  of  Neuralgia  and  Headache, 
especially  when  they  were  periodic  in  their  appearance,  and  good 
results  have  been  obtained  in  these  cases  and  also  in  others  where 
no  periodicity  could  be  observed.  Many  of  these  were  certainly  not 
of  malarial  origin,  and  no  explanation  of  the  action  of  quinine  here 
has  been  proposed.  Perhaps  the  lessened  formation  of  uric  acid  and 
other  poisonous  i)r{)ducts  may  be  suggested  as  a  possible  cause  of  the 
improvement. 

The  tinctures  of  cinchona  are  often  prescribed  as  Stomachic  Bitters, 
and  for  this  purpose  are  generally  fortified  by  preparations  of  nux 
vomica  or  of  the  simple  bitters. 

Quinine  has  been  a(h'ised  in  whooping-cough,  hay  fever  and  in- 
fluenza, and  in  fact  is  regarded  by  many  as  a  s})ecific  in  these  diseases, 
though  others  have  found  it  unreliable.  It  is  often  difficult  to  induce 
a  child  to  take  the  bitter  salts,  and  recourse  may  be  had  to  the  alka- 
loid itself,  euquinine,  or  the  tannate  disguised  with  sugar  or  chocolate. 
The  use  of  a  solution  as  a  wash  for  the  nose  in  hay  fever  was  brought 
into  i)rominence  by  Ilelmholtz,  who  gained  relief  in  this  way,  but 
it  has  not  proved  very  efficacious.  The  local  use  of  quinine  solutions 
and  of  cinchona  ])reparati()ns  is  also  advised  in  relaxed  throat  (gargle) 

'  Morni'iirotli  has  found  tliat  cthylliydrociipR'iiio,  a  dcrivalivc  of  one  of  tlic  ciiu'lioiia 
bases,  has  a  well-marked  beneficial  action  on  mice  infected  with  uneumococcus,  and  that 
its  previous  injection  protects  these  animals  from  infccfioii  It  does  not  appear  to  have 
any  such  remedial  action  in  pneumonia  in  man. 


QUININE  469 

and  ill  gonorrhoea  (urethral  injection).  It  has  sometimes  been  used 
as  an  antiseptic  externally,  but  is  too  expensive  for  ordinary  use. 

Quinine  has  been  advised  as  an  ecbolic  to  increase  the  contractions 
of  the  uterus  during  labor.  This  was  suggested  by  the  observation 
that  in  malarial  regions,  abortion  occasionally  occurred  after  quinine, 
and  many  observers  report  the  most  satisfactory  results  from  the 
treatment  of  uterine  inertia  with  one-gramme  doses  of  quinine,  and 
prefer  it  to  ergot  in  this  condition.  The  movements  of  the  uterus 
induced  are  practically  identical  with  those  occurring  naturally. 

Contra-indications. — ^Where  a  special  idiosyncrasy  exists,  quinine 
may  be  unsuitable,  but  these  cases  are  far  rarer  than  is  generally 
believed.  A  moderate  action  on  the  hearing,  for  example,  is  not  to 
be  considered  a  contra-indication,  although  in  those  cases  a  small  dose 
is  often  found  sufficient  in  malaria.  Where  an  inflammatory  condi- 
tion of  the  membranes  of  the  ear  already  exists,  quinine  ought  to  be 
administered  with  care,  or  avoided  entirely  if  possible,  The  addition 
of  bromides  is  often  found  to  lessen  or  remove  the  discomfort  arising 
from  the  disordered  hearing,  but  the  quantity  of  bromide  contained 
in  the  hydrobromide  of  quinine  is  insufficient  to  eftect  this,  and  the 
ordinary  potassium  salt  ought  therefore  to  be  prescribed.  Where 
very  marked  disturbance  of  the  digestion  exists,  quinine  is  often  liable 
to  augment  it,  owing  to  its  irritant  properties,  and  must  therefore  be 
given  with  caution  by  the  mouth,  or  perhaps  is  better  applied  hypo- 
dermically.  Hsemoglobinuria  following  the  administration  of  quinine 
indicates  that  the  dose  should  be  reduced.  Abortion  so  seldom  occurs 
after  quinine  that  pregnancy  is  no  objection  to  its  administration. 
In  general,  it  may  be  stated  that  quinine  is  often  credited -with  many 
disadvantages  which  it  does  not  possess,  and  that  in  cases  of  malaria, 
in  wdiich  it  is  practically  without  a  rival  or  substitute,  only  the  most 
pronounced  idiosyncrasy  can  justify  withholding  it.  In  other  cases, 
as  in  septic  fever,  it  may  be  a  question  whether  it  does  not  aggravate 
the  condition  when  it  is  administered  to  very  weak  patients. 

Bibliography. 

Binz.  Arch.  f.  mikros.  Anat.,  iii,  p.  383.  Virchow's  Archiv,  xlvi,  p.  67;  li,  p.  6.  Ex- 
perimentelle  Untersuch.  fiber  das  Wesen  der  Chininwirkung,  Berlin,  1868.  Arch.  f.  exp. 
Path.  u.  Pharm.,  i,  p.  18;    v,  p.  39;    vii,  p.  275. 

Wild.     Brit.  Med.  Joiirn.,  1887;    ii,  p.  500. 

Wood.     Therap.  Gazette,  Jan.,  1902.     (Skin  Eruptions.) 

Wittmaack.     Pfliiger's  Archiv,  xcv,  pp.  209,  234. 

Husemann.     Therap.  Monatshefte,  1888,  p.  7. 

Gottlieb.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxvi,  p.  419;    xxviii,  p.  167. 

Hertwig.     Jena.  Ztschr.  f.  Med.  u.  Naturwiss.,  xx,  pp.  120  and  477. 

Merkcl.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlvii,  p.  165. 

Santesson.  Ibid.,  xxx,  pp.  411  and  448;  xxxii,  p.  321.  Skand.  Arch.  f.  Physiologie, 
vii,  p.  385. 

Weber.     Ergebnisse  der  Physiologie,  iii,  1,  p.  262.     (Metaboh'sm.) 

Loewi.     Ibid.,  iii,  1,  p.  360.    (Temperature.) 

Talma  u.  v.  d.  Weyde.     Ztschr.  f.  klin.  Med.,  ix,  p.  276. 

Albertoni.     Arch.  f.  exp.  Path.  u.  Pharm.,  xv,  p.  248. 

Schumacher.     Arb.  a.  d.  pharm.  Inst,  zu  Dorpat,  x,  p.  1. 

Grethe.     Deutsch.  Arch.  f.  khn.  Med.,  Ivi,  p.  189. 


470  SUBSTANCES  ACTING  AFTER  ABSORPTION 

Maragliano.     Ztschr.  f.  klin.  Med.,  xiv,  p.  309;    xvii,  p.  291. 

Liepelt  and  Stuhlinger.     Arch.  f.  exp.  Path.  u.  Pharm.,  xliii,  pp.  151,  168. 

Pohl.     Arch.  f.  exp.  Path.  u.  Pharm.,  xli,  p.  111. 

De  Schweinilz.     Ainer.  Jouni.  of  the  Med.  Scicn.,  oxiv,  p.  2S2. 

Cavazzani.     Arch.  Ital.  do  Biol.,  xxxii,  p.  350. 

Ellram.     Arch,  internat.  de  Pharniacodyn.,  ix,  p.  289.     (Cinchonamiue.) 

Birch-Hirschfeld.     Arch.  f.  Ophthahnol.,  lii,  p.  358. 

Ward  Holden.     Arch,  of  Ophthal.  and  Otology,  Nov.,  1898. 

Katz.     Biochem.  Zeitschr.,  xxxvi,  p.  144. 

Giemsa  u.  Schumann.     Arch.  f.  Schiff  u.  Tropenhyg.,  xi.    Beiheft 

Rolh.     Journ.  of  Pharmacology,  iv,  p.  157. 

Moldovan.     Biochem.  Zeitschr.,  xlvii,  p.  421. 

Barrelt  and  York.     Annals  of  Trop.  Med.,  iii,  p.  1. 


XXXI.   THE  ANTIPYRETICS.     (ACETANILIDE  AND  ANTIPYRINE 

SERIES.) 

The  antipyretics  are  a  recent  addition  to  tlierapeutics,  tlie  oldest 
of  this  group  now  in  use  dating  only  from  1884.  Up  to  1875  the  only 
means  of  combating  high  temperature  were  batlis,  vegetable  alkaloids, 
such  as  quinine  and  aconitine,  or  alcoholic  preparations,  but  in  that 
year  Buss  discovered  that  salicylic  acid  produced  a  fall  in  the  fever 
temperature,  and  soon  afterward  carbolic  acid  and  resorcin  and  its 
isomers  were  employed  as  antipyretics.  A  very  large  number  of  anti- 
jn'retics  have  been  introduced  since  that  time,  but  most  of  them  have 
had  only  a  temporary  vogue,  and  those  in  general  use  at  the  present 
time  are  comparatively  limited  in  number. 

Quinine  is  a  quinoline  derivative,  and  quinoline  itself,  as  well  as  some  of  its 
simpler  compounds,  were  among  the  earlier  antipyretics  suggested.  Quinoline 
(C9H7N)  was  soon  found  to  be  dangerous  from  its  producing  collapse,  but  its 
derivatives  Kairine  (C9H9(OH)N— C2H5),  Kairoline  (C9H8(CH3)(OH)NH)  and 
ThaUine  (C9H9(OCH3)NH)  were  used  extensivel.v,  although  tlicj-  have  now 
been  entirely  abandoned;  Analgen  is  a  quinoline  derivative,  still  prescribed  to 
a  very  hmited  extent. 

A  new  antipyretic  was  introduced  in  1884  under  the  name  of  Antipyrine. 
wliich  is  derived  from  phenylhydrazine,  and  has  pro\-ed  superior  to  all  of  the 
earlier  drugs.  Phenylhydrazine  (CeHj — NH — NH-.)  produces  a  fall  in  the  fever 
temperature,  but  this  is  frequently  accompanied  by  collapse  and  changes  in  the 
blood,  which  prevents  its  use  in  medicine.  Several  of  the  simpler  compounds 
ha\'e  received  a  more  or  less  extensive  trial  as  antipyretics,  but  have  proved 
dangerous  and  inferior  to  Antipyrine,  phenyldimcthylpyrazolon, 

/NCH3— C(CHj) 
C6H6N< 

\C0— CH 

The  latter  is  still  very  largely  used  as  an  antipyretic,  either  in  it.s  original  form 
or  as  a  constituent  of  numerous  combinations  which  have  been  introduced  of 
late  years.  Among  these  may  be  mentioned  Pyramidon  (diniethylamino- 
antipyrine),  Ilypnal  (chloi-al  and  aniipyiine),  Salipyrinc  (salicylic  acid  and 
antipyrine). 

Antipyrine  early  found  a  rival  in  Antifebrine  or  Acetanilide,  wliich  wa.s 
advised  as  an  antipyretic  in  1886  by  C'ahn  and  Hep]).  Aniline  (C'clIsNII-..), 
from  whicli  it  is  derived,  has  also  some  action  on  the  temjierature,  but  like 
phenylhydrazine  i)roduces  dangerous  collapse  and  destruction  of  the  blood 
cells.  Acclanilidc  (CclbNlK'OCII^),  the  first  of  its  derivatives  to  be  intro- 
duced, is  not  entirely  devoid  of  this  ])ois()nous  action,  and  has  been  su])plaiitetl 
to  a  considerable  extent   by  more  (•oni])le\  and  less  poisonous  bodies.     One  of 


THE  ANTIPYRETICS  471 

these,  Exalgine  (C6H5NCH3COCH3),  differs  from  antifebrine  only  in  possess- 
ing a  nietli}'!  group  in  the  side  chain,  and  seems  to  resemble  it  closely  in  its 
effects.  It  was  soon  found  that  both  aniline  and  antifebrine  undergo  a  partial 
oxidation  in  the  body,  with  the  formation  of  amidophenol  or  its  derivatives,  and 
the  belief  that  the  antipjTetic  effects  were  due  not  so  much  to  the 
original  substance  as  to  these  oxidation  products  led  to  the  introduction 
of  numerous  derivatives  of  paramidophenol  (NH2 — C6H4 — OH).  This  body 
has  antipATCtic  properties  but  suffers  under  the  same  disadvantages  as 
aniline.  Among  its  derivatives  the  most  satisfactory  antipyretics  are  those 
in  which  the  hydrogen  of  the  hydroxyl  is  substituted  by  alkyl,  while  an  acid 
radicle  is  added  to  the  amido-radicle.  The  first  of  its  compounds  to  be  mtro- 
duced  was  Phenacetine  (COCH3NH— C6H4— OC2H5),  which  differs  from  anti- 
febrine onlv  in  the  addition  of  ethoxyl  in  the  para  position.  It  is  much  less 
dangerous  "than  acetanilide  and  antipyrine,  and  has  therefore  been  largely 
used,  and  has  been  followed  by  other  bodies  which  are  identical  with  it, 
except  in  the  acid  radicle  attached  to  the  nitrogen.  Among  these  phenetidines 
may  be  mentioned  Lactuphcnine  (lactyl-phenetidine),  Triphcnine  (propionyl- 
phenetidine),  Malakine  (salicyl-phenetidine),  and  Salophen,  which  contains 
similar  constituents,  Citrophen  (citryl-phenetidine) ,  Knjofinc  (methylglycolic- 
phenetidine),  and  Phcnocull  (glycocoll-phenetidine),  with  its  compound  with 
salicjdic  acid,  SalocoU. 

Several  urethane  derivatives  have  also  received  a  trial  as  antipyretics, 
among  them  being  Euphorine  (phenylurethane),  which  is  somewhat  poisonous, 
and  Thermodine  (phenacetine-urethane) . 

With  the  exception  of  antipyrine,  all  the  antipyretics  at  present  in 
use  probably  ow-e  their  activity  to  the  formation  of  simple  derivatives 
of  paramidophenol  in  the  tissues,  and  differ  chiefly  in  the  rapidity  with 
which  this  decomposition  occurs.  A  rapid  formation  of  paramidophenol 
produces  destructive  blood  changes  and  a  tendency  to  collapse,  while  the 
antipyretic  effects  pass  off  very  rapidly.  Those  drugs  are  found  the 
most  satisfactory  antipyretics  in  which  the  decomposition  proceeds 
gradually,  so  that  the  temperature  falls  slowdy  and  remains  low  for  a 
longer  time.  The  simpler  antipyretics,  such  as  antifebrine,  have  given 
way  largely  therefore  to  the  phenetidine  compounds.^  Among  these 
it  is  impossible  to  determine  the  most  suitable  antipyretic,  but  none 
of  them  has  been  proved  to'be  superior  to  phenacetine.  Where  the  merits 
seem  so  equally  divided,  it  is  perhaps  more  important  to  learn  to  use 
one  with  judgment  than  to  hurry  after  each  new  product  without 
sufficient  experience  of  its  predecessor. 

Symptoms. — The  effects  of  the  antipyretics  vary  not  only  with  the 
dose  but  with  the  individual  patient.  ]\Iany  persons  can  take  very  large 
doses  without  apparent  effect,  while  in  others  comparatively  minute 
quantities  produce  symptoms  of  greater  or  less  importance.  The 
effects  are  not  always  the  same,  even  in  one  individual  under  the 
same  dose  of  the  antipyretic,  and  it  is  impossible  to  state  at  present 
what  are  the  conditions  that  involve  the  peculiar  train  of  symptoms. 
A  very  large  number  of  disorders  have  been  attributed  to  the  anti- 
pyretics in  man,  but  it  is  impossible  to  consider  any  here  except  those 
more  commonly  observed.    Among  these  are  skin  eruptions  of  various 

1  For  a  detailed  discussion  of  these  principles  see  V.  Mering,  Therap.  Monatsh.,  1893, 
p.  577,  and  Hinsberg  and  Treupel,  Arch.  f.  e*xp.  Path.  u.  Pharm.,  xxxiii,  p.  216. 


472  SUBSTANCES  ACTING  AFTER  ABSORPTION 

forms,  such  ;is  red,  (erythematous,  itchinf]^  patches  or  more  widely 
(Hflused  hyjjcra'mia  resembUnn'  tlie  onset  of  measles  or  scarlatina; 
urticaria  occurs  not  uncommonly,  while  eczema  and  bulhe  are  rarer. 
In  some  cases  an  oedematous  swelling  has  been  obse^^'ed.  Some  fever 
occasionally  accompanies  the  eruption  and  renders  the  diagnosis  from 
the  infectious  exanthemata  even  more  difficult.  These  skin  afi'ec- 
tions  seem  to  be  elicited  more  frequently  by  antipyrine  than  by 
acetanilide  and  the  phenetidine  compounds.  They  haAC  been  attributed 
to  dilatation  of  the  cutaneous  vessels,  but  this  in  itself  is  insufficient 
to  explain  their  appearance,  although  it  may  be  a  favoring  condition. 
Profuse  per.s'pirafion  not  infrequently  follows  the  use  of  the  anti- 
pyretics in  fever,  and  if  the  fall  in  temperature  be  rapid,  and  the 
action  of  the  drug  passes  off  soon,  the  subsequent  rise  of  temperature 
may  be  accompanied  by  shivering  and  rigor,  but  these  symptoms  are 
scarcely  to  be  looked  upon  as  direct  effects  of  the  drug,  but  rather  as 
resulting  from  the  rapid  changes  in  temperature.  They  are  produced 
much  more  frecjuently  by  the  older  and  simpler  anti])yretics  than  by 
those  of  more  recent  introduction. 

Sometimes  catarrh,  burning  and  swelling  of  the  throat  and  mouth 
are  observed  after  antipyrine,  and  more  rarely  nausea  and  I'omitiug. 
CerrhraJ  synipfoins  are  rarely  elicited  beyond  slight  dulness,  confusion 
or  apathy.  Alterations  of  the  hearing  similar  to  those  described  under 
quinine  have  been  observed  in  some  cases.  More  serious  symptoms 
are  those  of  collapse,  which  are  occasionally  produced  in  susce])tible 
{persons,  especially  by  large  doses.  Acetanilide  is  much  more  liable  to 
elicit  these  than  antipyrine,  which  in  turn  is  more  dangerous  than 
phenacetine  and  the  other  phenetidine  derivatives.  In  the  milder  cases 
of  collapse  the  skin  is  cool,  the  pulse  is  rather  small  and  rapid,  and  some 
anxiety  and  alarm  is  felt  by  the  patient,  but  the  condition  passes  off 
in  a  short  time.  In  more  severe  cases  the  skin  is  cold  and  covered  by  a 
clammy  persiration,  the  heart  is  weak,  irregular  and  sometimes  fluttering, 
the  temperature  may  be  subnormal  and  the  pupils  are  slightly  dilated. 
The  patient  may  be  conscious,  fainting  may  occur,  or  an  apathetic, 
confused  condition  may  be  produced.  The  weakness  of  the  heart  is 
the  chief  source  of  anxiety,  and  the  total  failure  of  the  circulation 
seems  to  be  the  cause  of  death.  These  cases  of  collapse  occur  more 
frequently  when  a  rapid  fall  of  temperature  has  been  produced  than 
under  other  circumstances,  l)ut  may  be  observed  in  cases  in  which  no 
fever  has  been  ])resent. 

Marked  ci/anosis  occurs  occasionally  under  all  the  antipyretics,  but 
more  frequently  under  acetanilide  and  the  earlier  members  of  the 
series  than  under  antipyrine  and  the  phenetidine  compounds.  Its 
chief  cause  apjjcars  to  be  the  formation  of  methaMuoglobin  in  the 
blood,  although  it  is  said  to  have  been  i)resent  in  some  cases  in  which 
this  pigment  could  not  be  recognized,  and  it  is  often  more  intense 
than  that  obser\-ed  from  the  action  of  other  poisons  which  lead  to  the 
formation  of  met  haemoglobin;  this  suggests  that,  in  some  cas(>s  at 
least,  the    cNanosis    arises    from    feebleness    of  the    circulation    rather 


THE  ANTIPYRETICS  473 

than  from  changes  in  the  blood  i)ignieiit.  It  is  often  accompanied  by 
dyspnoea  and  acceleration  of  the  pulse,  and  it  lasts  for  a  \arying 
length  of  time,  sometimes  passing  off  in  a  few  hours,  at  other  times 
persisting  for  several  days. 

Occasionally  a  certain  tolerance  is  gained,  and  larger  doses  of  the 
antipyretics  are  required  to  produce  effects  than  were  necessary  at  the 
beginning  of  the  treatment.  ]\Iany  cases  of  chronic  poisoning  are 
recorded  from  the  habitual  use  of  acetanilide.  The  symptoms  con- 
sist in  disturbance  of  the  digestion,  cyanosis,  tremor,  muscular  weak- 
ness and  general  mental  debility;  the  blood  is  often  chocolate-colored 
from  the  formation  of  methsemoglobin,  and  the  urine  often  contains 
hjiemoglobin,  or  its  products,  or  may  be  colored  by  the  oxidation 
products  of  paramidophenol.  The  condition  is  sometimes  difficult  to 
recognize,  especially  as  the  patient  may  deny  that  the  drug  has  been 
taken.     The  symptoms  disappear  rapidly  w^ien  the  drug  is  given  up. 

These  drugs  are  by  no  means  very  poisonous,  normal  anhnals  showing  no 
reaction  to  doses  which  are  sufficient  to  cause  marked  changes  in  iexer.  In 
the  frog  Antipyrine  causes  an  increase  in  the  refiex  irritability,  which  some- 
times leads  to  tetanic  convulsions  and  is  followed  by  depression,  loss  of  the 
^'oluntary  movements,  and  eventually  by  complete  paralysis  and  death.  In 
mammals  its  injection  is  followed  at  first  by  a  period  of  quiet  and  sometimes 
of  somnolence,  which  is  said  by  some  authors  to  occur  also  in  the  frog  previous 
to  the  increase  in  the  reflex  irritability.  Some  rise  in  the  reflex  irritability  may 
be  made  out  in  the  mammal  at  this  stage,  and  large  doses  cause  convulsions 
and  tremors,  and  subsequently  unconsciousness  and  collapse,  ending  in  com- 
plete paralysis.  The  pulse  is  accelerated  by  small  doses,  while  in  the  later 
stages  of  poisoning  it  may  be  slow,  and  some  dilatation  of  the  skin  vessels 
and  flushing  have  been  observed.  The  respiration  is  at  first  accelerated,  and 
then  becomes  slow  and  irregular  when  large  doses  are  injected.  In  dogs  vomit- 
ing and  dilatation  of  the  pupil  generally  occur. 

Antifebrine  is  more  poisonous  than  antipjTine  in  both  frogs  and  mammals, 
but  resembles  it  in  its  general  effects,  producing  first  a  more  or  less  marked 
stage  of  lessened  activity,  foUowed  by  convulsive  movements.  The  respira- 
tion is  not  so  much  accelerated  as  b}'  antipyrine,  and,  according  to  some  ob- 
servers, is  slow  from  the  beginning  of  the  action.  The  heart  is  first  accelerated 
and  then  slow  and  irregular,  and  cyanosis  and  collapse  are  more  frequently 
observed  than  under  antipyrine.  Phenacetine  and  its  allies  are  much  less 
poisonous  than  the  two  foregoing,  but  in  large  quantities  produce  almost 
identical  effects — somnolence  followed  by  convulsions,  cyanosis,  and  coUapse 
symptoms,  first  rapid,  then  slow  respiration  and  heart.  Lactophenine  is  said 
to  have  a  more  sedative  effect  than  the  other  antipyretics,  and  to  induce  com- 
plete narcosis  in  the  rabbit. 

Action. — The  action  of  these  drugs  on  the  various  organs  is  very 
imperfectly  understood.  The  Nerve  Centres  are  affected,  as  is  shown 
by  very  slight  somnolence  occasionally  in  animals  and  also  in  man, 
but  much  more  frequently  by  the  relief  of  pain  as  in  neuralgia  and 
headache;  this  is  generally  attained  without  any  observable  depres- 
sion of  mental  activity  and  is  therefore  quite  distinct  from  the  anal- 
gesia obtained  by  the  use  of  morphine  or  antesthetics.  This  suggests 
that  the  antipyretics  relieve  pain  by  affecting  not  the  cerebral  cortex, 
but  some  lower  point,  which  may  be  assumed  to  be  a  synapse  on  the 


474  SUBSTANCES  ACTING  AFTER  ABSORPTION 

path  conveying  pain  sensations;  there  are  two  of  these,  one  in  the 
spinal  cord  and  one  in  the  thalamus,  and  as  the  antipyretic  action  of 
this  fjroup  is  due  to  changes  in  the  neighborhood  of  the  latter,  it  seems 
likely  that  their  action  in  abating  pain  may  be  located  here  also  (Head). 

]\Iost  of  the  antipyretics  increase  the  excitability  of  the  spinal  cord 
at  first,  and  this  may  lead  to  convulsions  in  the  frog.  The  origin  of  the 
convulsions  in  mammals  is  still  somewhat  doubtful;  in  general,  they 
seem  to  be  of  cerebral  origin,  but  when  large  quantities  are  injected 
they  are  seen  even  when  the  spinal  cord  is  divided  from  the  brain,  so 
that  the  cord  appears  to  ])e  thrown  into  a  condition  resembling  that 
discussed  under  strychnine  poisoning.  In  considering  the  cause  of 
these  convulsions  perhaps  too  little  weight  has  been  laid  by  some 
writers  on  the  changes  in  the  blood,  respiration  and  circulation,  for 
it  is  possible  that  the  convulsions  in  some  cases  are  asphyxial  in  char- 
acter, and  not  due  to  the  direct  action  of  the  poisons  on  the  brain. 

In  ordinary  poisoning  the  peripheral  Nerves  and  nerv^e  ends  do  not 
seem  to  be  seriously  involved,  and  the  final  paralysis  in  both  frogs  and 
mammals  is  undoubtedly  central.  Santesson  found  that  antipyrine 
tended  to  increase  the  power  of  the  frog's  Muscles,  and  several  observers 
have  noted  that  the  nerves  and  motor  terminations  are  paralyzed  by  the 
direct  application  of  this  drug.  Antipyrine  has  some  effect  as  a  local 
anaesthetic  when  applied  to  the  mucous  membranes. 

The  Heart  in  the  frog  and  mammals  is  first  accelerated  and  then 
slowed  by  the  antipyretics  in  general,  these  alterations  being  entirely 
independent  of  the  inhibitory  mechanism  and  due  to  a  direct  efl'ect  on 
the  cardiac  muscle.  The  increased  rhythm  of  the  heart  leads  to  a 
slight  rise  in  the  blood-pressure,  which  sinks  again  as  the  pulse  becomes 
slower.  There  is  no  satisfactory  proof  that  the  vaso-motor  centres  are 
involved  in  the  rise  of  pressure,  although  it  is  not  unlikely  that  they 
undergo  a  primary  stimulation  at  the  same  time  as  the  respiratory 
centre. 

Most  of  this  series,  except  antipyrine  and  its  compounds,  tend  to 
cause  alterations  in  the  Red  Blood  Cells  when  they  are  given  in  large 
quantities.  This  action  is  manifested  especially  by  the  simpler  bodies 
of  the  series,  and  is  still  more  marked  in  poisoning  from  aniline, 
phenylhydrazine,  paramidophenol  or  quinoline.  On  the  other  hand, 
most  of  the  phenetidine  compounds  produce  it  much  more  rarely,  and 
antipyrine  seems  devoid  of  this  action.  The  alteration  consists  in  the 
formation  of  metluemoglobin,  which  may  be  readily  detected  by  its 
characteristic  spectroscopic  appearance.  Small  quantities  of  the  anti- 
pyretics cause  its  formation  within  the  blood-cells,  which  remain 
intact,  but  larger  doses,  especially  of  the  more  ])oisonous  members, 
destroy  the  red-blood  cells  and  free  the  metluemoglobin  in  the  plasma. 
In  the  blood  various  distorted,  shrunken  red  cells  may  be  observed, 
often  entirely  devoid  of  coloring  matter,  while  part  of  the  methaemo- 
globin  seems  to  escape  through  the  kidneys,  and  ne})hritis  occurs  in 
sonic  cases  with  albumin,  h;rniogl()l)in  and  even  blood  in  the  urine. 
This  cH'cct  on  the  bhiod  seems  due  to  tin*  decomposition  of  the  aiiti- 


THE  ANTIPYRETICS  475 

pyretics  and  the  flooding  of  the  tissues  with  paramidophenol,  or  the 
corresponding-  quinohne  derivative.  This  decomposition  proceeds  more 
slowly  in  plienacetine  and  its  allies  and  is  absent  after  antipyrine, 
which  explains  the  rarity  of  the  symptoms  after  these  drugs.  When 
the  antipyretics  are  added  to  blood  outside  the  body  no  meth.iemoglobin 
is  formed,  as  this  effect  arises  from  only  their  decomposition  products. 

All  of  the  antipyretics  have  some  Antiseptic  action,  which  varies^  in 
the  ditierent  members  with  their  solubility  and  stability.  Antipyrine 
is  found  to  preserve  blood  from  putrefaction  for  some  days  when 
added  to  it  so  as  to  form  a  solution  of  2-5  per  cent.  Watery  solutions 
of  this  strength  destroy  protozoa  and  stop  the  movements  of  the 
leucocytes,  but  antipyretics  administered  to  the  higher  animals  have 
no  such  effect  on  the  emigration  of  the  leucocytes  from  the  vessels  as 
is  seen  under  quinine. 

The  action  of  the  antipyretics  on  the  Metabolism  of  healthy  men 
and  animals  has  been  the  subject  of  a  number  of  investigations  which 
have  given  by  no  means  uniform  results,  especially  in  regard  to  the 
nitrogen  elimination.  Antipyrine  has  no  influence,  or  only  an  insig- 
nificant one,  on  the  metabolism  of  the  healthy  tissues,  whether  this 
be  measured  by  the  nitrogenous  excretion  or  by  the  gaseous  exchange 
in  the  lungs. 

Antifebrine,  on  the  other  hand,  has  a  distinct  effect  on  the  nitrogen 
eliminated,  although  this  is  only  elicited  by  large  doses.  After  ordi- 
nary quantities  the  urea  and  total  nitrogen  of  the  urine  may  be  slightly 
augmented,  but  in  large  doses  antifebrine  causes  an  increase  of  30-35 
per  cent,  in  these,  which  indicates  a  large  increase  in  the  tissue  waste. 
The  other  antipyretics  have  not  been  examined  so  carefully.  The  ex- 
change of  gases  in  the  lungs  is  not  aftected  by  the  antipyretics  in  healthy 
animals,  and  no  definite  change  has  been  observed  in  the  excretion  of 
uric  acid. 

The  specific  effects  of  the  antipyretics  on  the  Temperature,  while 
recognized  by  all,  have  been  the  subject  of  endless  discussion,  owing 
to  the  complex  mechanism  through  which  they  are  elicited.  In  the 
normal  animal  the  temperature  is  but  little  altered,  except  by  doses 
large  enough  to  produce  collapse,  but  when  it  is  abnormally  high,  as 
in  fever,  the  antipyretics  cause  a  fall  of  greater  or  less  extent.  _  This 
fall  in  temperature  occurs  at  varying  intervals  after  the  ingestion  of 
the  drug,  but,  except  in  refractory  cases,  always  begins  within  2-3 
hours.  Its  extent  varies,  the  temperature  sometimes  reaching  the 
normal  or  even  a  subnormal  point,  while  in  others  the  change  is  insig- 
nificant. Continuous  fever  without  any  natural  rise  and  fall  is  much 
less  aflfected,  as  a  general  rule,  than  one  with  alternate  rise  and  fall 
of  the  temperature,  and  in  the  latter  form  the  result  is  much  greater  if 
the  drug  be  given  at  the  beginning  of  one  of  the  natural  remissions. 

The  fall  in  temperature  is  often  accompanied  by  flushing  of  the 
skin  and  perspiration.  The  oxygen  absorbed  and  the  carbonic  acid 
excreted  are  lessened,  and  the  urea  and  nitrogen  of  the  urine  are  also 
diminished  after  antipyrine,  while  they  are  not  infrequently  increased 


476  SUBSTANCES  ACTING  AFTER  ABSORPTION 

after  antifebrine,  especially  when  a.  1  ministered  in  large  quantities.' 
The  heart  is  often  reduced  in  rate,  and  the  ])ulse  improves  in  strength, 
but  these  changes  are  due  to  the  fall  in  the  temperature  and  not  to 
the  direct  action  of  the  drugs.  Some  remedies  owe  their  antii)\Tetic 
properties  to  their  increasing  the  secretion  of  the  sweat  glands,  but 
although  perspiration  not  infrequently  occurs  during  the  fall  of  tem- 
perature under  the  new  antipyretics,  this  is  merely  a  secondary  result 
here,  for  when  the  perspiration  is  checked  by  atropine  or  agaricin,  the 
fall  of  temperature  proceeds  uninterruptedly. 

The  temperature  in  healthy  warm-blooded  animals  is  kept  uniform 
through  a  balance  being  estal)lished  between  the  heat  formation  and  its 
dissipation  through  the  lungs,  skin,  and  other  organs.  If  an  excessive 
formation  occurs,  as  during  muscular  exertion,  this  is  counterbalanced 
by  an  increase  in  the  output  from  the  skin  through  the  dilatation  of 
the  vessels  and  by  the  perspiration.  If,  on  the  other  hand,  more  heat  is 
dissipated  than  usual  through  exposure  to  cold,  the  combustion  of  the 
tissues  is  increased  and  more  heat  is  formed.  The  output  of  heat  is 
thus  determined  by  the  degree  of  dilatation  of  the  cutaneous  \essels 
and  the  activity  of  the  sweat  glands,  while  the  amount  of  heat  formed 
varies  with  the  voluntary  and  involuntary  contractions  of  the  muscles. 
In  order  to  preserve  a  balance  between  these  two  factors,  there  must 
exist  a  coordinating  mechanism,  and  this  is  supposed  to  be  located  in 
the  basal  ganglia  of  the  cerebrum,  in  the  neighborhood  of  the  ventricles. 
Lesions  in  this  neighborhood  generally  cause  a  very  marked  rise  in 
the  temperature,  often  without  further  disturbance,  and  it  is  of  inter- 
est to  learn  that  as  long  as  the  cerebrum  is  intact,  shivering  is  ])ro- 
duced  by  cold,  while  after  the  section  of  the  peduncles  the  animal 
offers  no  resistance  to  a  fall  of  temperature  produced  by  cooling  of 
the  surface. 

Other  facts  might  also  be  adduced  to  show  that  in  the  normal  animal 
the  temperature  is  kept  uniform  by  this  coordinating  mechanism, 
which  controls  both  the  output  of  heat  through  the  skin  and  its  for- 
mation by  the  contractions  of  the  skeletal  muscles.  In  many  intli- 
vidials  this  coordination  is  not  perfect  in  health,  and  in  all  it  may 
l)e  disorganized  })y  ])oisons,  such  as  those  formed  in  fever.  The  more 
perfect  the  coordination,  the  smaller  is  the  divergence  from  the  normal 
temperature  necessary  to  elicit  a  protective  increase  in  the  combustion 
or  in  the  dissipation.  The  efficiency  of  the  mechanism  may  therefore 
be  measured  by  observing  what  fall  of  the  body  temjierature  occurs 
before  shivering  sets  in,  what  rise  ])ro(luces  dilatation  of  the  cutaneous 
vessels  and  i)erspiration.  In  this  way  it  has  been  found  that  during 
fever  the  coordination  is  quite  as  perfect  as  in  health,  but  tluU  the 
protective  reactions  are  induced  at  a  higher  temperature.  Thus. 
Kichter  found  that  a  normal  dog  (temperature  o8.()°  C.)  protected 
itself  by  shivering  when  its  temperature  was  reduced  by  cold  to  o7.0,° 

'  Even  when  the  nitrogenous  metabolism  is  reduced  by  antipyretics  in  fever,  it  is 
said  to  be  remarkably  increased  as  the  temperature  rises  again,  so  that  no  real  economy 
of  proteins  results  from  their  u.se. 


THE  ANTIPYRETICS  477 

while  profuse  perspiration  broke  out  when  its  temperature  was  raised 
to  39.1°.  The  same  dog  suffering  from  fever  (temperature  40.4°  C.) 
reacted  by  shivering  when  its  temperature  was  reduced  to  40.2°  and 
by  perspiration  when  it  rose  to  40.9°.  The  coordination  is  not 
destroyed  or  paralyzed  by  fever  therefore,  for  it  is  in  this  case  more 
sensitive  to  alterations  of  the  body  temperature  than  in  the  normal 
animal.  The  same  measures  are  taken  to  preserve  a  uniform  temper- 
ature as  in  health,  but  the  temperature  maintained  by  these  means  is 
higher.  If  a  comparison  be  made  with  the  thermostat  of  the  labora- 
tory, it  may  be  said  that  in  fever  the  mechanism  is  "set"  for  a  higher 
temperature  than  in  normal  life,  but  that  the  apparatus  acts  efficiently 
for  each  temperature.  This  higher  temperature  is  maintained  by  an 
increased  metabolism  or  heat  formation,  and  also  in  most  cases  by  a 
lessened  dissipation.  The  fever  temperature  itself  seems  to  increase 
the  metabolism,  the  tissues  undergoing  more  rapid  waste  under  it  than 
in  normal  conditions.^  The  coordinating  mechanism  appears  to  be  more 
susceptible  in  fever  to  various  influences,  and  the  consequent  varia- 
tions in  its  activity  cause  the  large  undulations  of  the  temperature 
curve  which  are  characteristic  of  pyrexia.  Among  these  influences 
is  the  temperature  itself,  for  Barbour  has  shown  that  the  overheated 
blood  tends  to  change  the  activity  of  the  centre  so  that  the  heat  loss  is 
augmented. 

The  antipyretics  do  not  lower  the  temperature  by  reducing  the 
heat  production,  for,  though  the  nitrogen  eliminated  and  the  oxygen 
absorbed  fall  during  their  action  in  fever,  this  lessened  tissue  waste  is 
the  result  not  the  cause  of  the  fall  of  temperature,  the  metabolism 
proceeding  more  slowly  when  the  heat  is  reduced. 

Calorimetric  investigations  have  shown  that  the  dissipation  of  heat 
in  fever  is  much  increased  by  the  antipyretics,  while  in  health  they 
seem  to  have  little  effect.  This  augmentation  in  the  output  is  due  to 
dilatation  of  the  cutaneous  vessels,  which  exposes  a  large  amount  of 
blood  to  the  cold  air.  The  dilatation  is  great  enough  to  be  recorded 
by  the  plethysmograph  in  many  cases,  while  in  others  flushing  of  the 
skin  may  be  observed.  The  increased  dissipation  of  heat  is  accompanied 
by  a  lessened  formation  which,  however,  is  much  less  important  and 
which  is  generally  attributed  to  the  metal)olism  i)roceeding  less  actiA-ely 
at  the  lower  temperature.  In  other  words,  the  antipyretics  reduce  the 
temperature  by  increasing  the  output  of  heat,  and  the  cells  of  the 
body  grow  and  change  less  when  removed  from  the  hot-house  tempera- 
ture to  which  they  have  been  exposed  })reviously.  It  must  be  added, 
however,  that  some  observers  hold  that  the  fall  in  heat  formation  is  too 
great  to  be  explained  in  this  way,  and  suppose  that  the  antipyretics 
lessen  the  combustion  through  some  other  action,  but  not  by  affecting 
the  tissues  directly. 

'  It  must  not  be  supposed  from  the  foregoing  statements  that  fever  consists  only  in  an 
alteration  of  the  normal  temperature.  This  is  only  one  of  the  symptoms  produced  by 
the  poisons  of  fever,  but  is  the  only  one  affected  by  the  antipyretics. 


478 


SUBSTANCES  ACTING  AFTER  ABSORPTION 


It  has  been  stated  already  that  the  fevered  animal  resists  any  change 
in  its  tonii)eratnre  in  the  same  way  as  the  normal,  and  it  might  there- 
fore l)e  expected  that  when  the  temi)erature  is  reduced  l)y  antipyretics 
the  organism  would  at  once  increase  its  heat  formation.  The  fact 
that  this  does  not  occur,  but  that,  on  the  contrary,  the  metabolism  is 
lessened,  indicates  that  some  further  change  occurs,  that  the  anti- 
pyretics not  only  reduce  the  temperature  by  allowing  the  heat  to 
escape,  but  also  alter  the  condition  of  the  coordinating  mechanism  by 
which  the  temperature  is  kept  uniform.  To  return  to  the  comparison 
with  a  thermostat,  the  body  temperature  is  set  at  a  lower  point  by  the 
antipyretics,  while  it  is  set  higher  by  the  fever  poisons. 

The  action  of  the  antipyretics  on  this  coordinating  centre  is  there- 
fore of  interest,  and  has  been  examined  both  in  health  and  disease. 
In  healthy  men  the  temperature  does  not  undergo  any  marked  change 
under  the  antipyretics,  for  though  it  may  fall  a  few  tenths  of  a  degree 


Fig,  64 

12          3         4         5         6 


9        10        11        13 


1  J 

ANTIPY 

RINE 

/ 

--^ 

k 

/> 

V 

^ 

r*- 

^^ 

^ 

r-* 

/ 

/ 

V- 

1 

> 

,^ 

/y 

,* 

■ 

\ 
i 

J 

,'' 

\/ 

t 

b 

Tcnipf-raturc  (;harts  of  two  rabbits  under  fever  toxins.  The  unbroken  line  was  obtained 
from  an  untreated  animal,  the  dotted  Hne  from  one  which  received  antipyrine  at  the  point 
indicated  by  an  arrow.  The  time  is  given  in  hours  along  the  horizontal  line;  the  tem- 
perature in  degrees  Centigrade  on  the  vertical.     (After  Kiliani.) 

in  some  cases,  this  is  of  no  significance.  The  sensitiveness  of  the 
coordinating  centre  is  increased  apparently,  however,  for  in  some 
individuals  in  whom  hard  muscular  work  causes  a  rise  of  temperature 
normally,  this  is  absent  or  less  marked  after  the  antipyretics.  In  tlu> 
same  way  the  rise  of  temperature  which  occasionally  is  caused  by 
very  hot  baths,  is  absent  or  diminished  when  antipyrine  has  been 
administered  i)reviously.  When  the  basal  ganglia  are  cut  off  from 
their  connections  with  the  lower  i)art  of  the  body,  neither  septic  in- 
jections nor  antipyretics  have  any  efiect  on  the  temi^erature,  while 
after  section  above  the  basal  ganglia,  fever  is  caused,  and  the  anti- 
pyretics induce  the  usual  fall  of  temi)erature  (Sawadowsky).  In  experi- 
ments in  which  high  fe\cr  was  ])ro(luced  by  lesions  in  the  neighbor- 
hood of  the  ganglia,  Gottlieb  found  that  the  antipyretics  reduced  the 
temperature  and  increased  tlu^  outjjut  of  heat  to  a  marked  extent, 
while  llic  fornialioii  was  increased  to  a  U^ss  degree. 


THE  A  N  TIP  YRETICS 


479 


Fig.  65 


c 

41 

40 

39 

38 

37 

36 

35- 

^-^ 

34 

\ 

33 

\ 

31 


30 


Finally,  the  coiulition  of  the  centre  has  been  examined  by  Stern  and 
Uichter  after  the  temperature  had  been  reduced  by  antipyretics.  They 
both  found  that  the  protective  mechanism  was  called  into  play  when 
the  temperature  was  slightly  raised,  and  generally  when  it  was  depressed. 
For  example,  a  fevered  dog  (temperature  40.9°  C.)  received  an  anti- 
pyretic, and  its  temperature  was  reduced  to  37.6°.  Attempts  were 
now  made  to  raise  the  temperature  by  external  heat,  but  the  animal 
resisted  this  by  increasing  the  output  as  soon  as  the  temperature  rose 
to  37.8°.  The  coordination  which 
maintained  the  temperature  at  40.9° 
before  the  drug  was  administered 
now  attempted  to  keep  it  at  37.6°. 

The  results  of  these  researches 
may  be  summed  up  shortly  as  fol- 
lows: The  antipyretics  reduce  the 
temperature  in  fever  through  alter- 
ations effected  in  the  heat-regulating 
nervous  mechanism,  which  result 
in  lowering  the  point  at  which  the 
temperature  is  maintained.  As  a 
consequence  of  this  action,  a  great 
increase  in  the  dissipation  of  heat 
must  occur  in  order  to  free  the 
body  from  the  warmth  which  it 
has  accumulated,  and  this  increased 
output  is  attained  by  dilatation  of 
the  cutaneous  vessels.  The  seat  of 
action  of  the  antipyretics  is  prob- 
ably situated  in  the  base  of  the 
cerebrum. 

The  action  of  the  antipyretics  is 
often  conceived  as  a  narcosis  of  the 
temperature-regulating  mechanism, 
which  is  excited  by  the  fever  poisons ; 
the  antipyretics  may  thus  be  re- 
garded as  acting  as  antagonists  to 
these   toxins   in   the  brain   in  the 

same  way  as  atropine  antagonizes  pilocarpine  in  the  heart.  The  lessened 
activity  of  the  narcotised  centre  leads  to  a  less  acti\e  constriction  of  the 
skin  vessels  and  thus  to  a  larger  loss  of  heat.  The  centre  poisoned  by  the 
toxins  is  apparently  more  readily  acted  on  than  in  the  normal  condition. 
There  is  some  evidence  for  the  narcotic  action  of  the  antipyretics,  but  this 
^•iew  is  purely  speculative  at  present  and  need  not  be  further  discussed. 

When  the  temperature  is  depressed  too  rapidly  by  these  remedies, 
a  condition  of  collapse  is  often  produced,  while  in  other  cases  the 
loss  of  heat  caused  by  the  dilatation  of  the  skin  vessels  seems  to  be 
excessive,  and  shivering  and  rigor  follow  in  order  to  increase  the  pro- 
duction. 


P  1 


B 


Curve  of  internal  temperature  (unbroken 
line)  and  of  the  skin  temperature  (dotted 
line)  in  fever  treated  with  antipyrine 
(Rosenthal).  The  abscissa  AB,  represents 
the  time  in  hours;  the  vertical,  AC,  the 
temperature  Centigrade.  At  P,  antipyrine 
was  given,  and  the  skin  temperature  rose 
at  once  (augmented  heat  output).  The 
internal  temperature  soon  began  to  fall, 
and  after  it  had  reached  a  certain  point 
the  skin  temperature  fell  again  as  the 
capillaries  contracted. 


480  SUBSTANCES  ACTING  AFTER  ABSORPTION 

\\\]v\\  tlic  tciiiiKTature  has  reached  the  new  point  fixed  by  the  coor- 
dination under  tlie  infinence  of  the  antipyretics,  the  heat  dissipation 
ra{)idly  (Uniinishes  and  may  l)ecome  less  than  normal,  because  the 
new  temperature  is  maintained  at  a  constant  point  by  the  same  mech- 
anism as  the  normal. 

The  antipyretics  are  rapidly  absorbed,  and  as  rapidly  Excreted  by 
the  kidneys,  so  that  they  disappear  from  the  body  within  2-t  oO  hours 
after  their  administration. 

The  fate  of  antipyrinc  seems  to  dilTer  in  different  animals.  In  the  dog  it 
is  found  to  be  partially  oxidized  to  oxyaiitipyrine  which  is  excreted  in  the 
urine  in  combination  with  glycvu-onic  and  sulphuric  acids.  In  others  it  is 
said  to  be  excreted  in  the  urine  vuichangcd.  Antifebrine  undergoes  a  partial 
oxidation,  the  final  product  differing  in  different  animals,  but  none  of  the 
original  body  appears  in  the  urine  except  after  very  large  doses.  In  man  it 
appears  as  acetylparamidophenol  (OH— C6H4— NHC2H3O)  and  as  paramido- 
phenol  or  another  of  its  compounds,  l)oth  l^eing  in  coml^ination  with  sulphuric 
and  glycuronic  acids.  In  the  rabbit's  urine  paramidophenol  alone  is  found,  while 
in  the" dog  this  is  accompanied  by  oxycarbanil  (C6H4O.NH.CO);  in  each  case 
it  forms  a  doul)le  sulphate  or  glycuronate.  The  fate  of  the  other  antipyretics 
rcscml)les  that  of  antifebrine,  the  quinoline  derivatives  undergoing  a  partial 
oxidation  resulting  in  a  body  analogous  to  paramidophenol,  while  the  phene- 
tidiue  compounds  are  partially  decomposed  and  appear  in  the  urine  as  glycu- 
ronatcs  of  pheuetidine.  The  combinations  containing  salicylic  acid  break  up 
in  the  body,  and  the  acid  appears  in  the  urine  as  salicyluric  acid,  while  the 
rest  of  the  molecule  undergoes  the  usual  partial  oxidation. 

The  presence  in  the  urine  of  these  bodies,  or  rather  of  further 
products  of  their  oxidation,  gives  it  a  dark,  reddish-brown  color,  which 
may  be  observed  when  it  is  passed,  or  more  frequently  after  it  has 
been  exposed  to  the  air  for  some  time. 

Preparations. 

Antipyrina  (U.  S.  p.),  Phenazonum  (B.  P.)  phenazone,  or  antipyrine, 
forms  colorless  inodorous  crystals,  with  a  bitter  taste,  very  soluble  in  water, 
alcohol,  and  chloroform.    0.25  G.  (4  grs.);   B.  P.,  5-15  grs. 

Phenacetinum  (B.  p.),  Acetphenetidinum  (U.  S.  P.),  colorless,  tasteless 
crystals,  insolul)le  in  water,  0.5  G.  {7\  grs.);  B.  P.,  5-15  grs.;  given  in  powders, 
cachets,  tal)lets,  or  suspended  in  mucilage. 

Acdnnilidum  (U.  S.  P.,  B.  P.),  acetanilidc  or  antifebrine,  colorless  crystals 
insoluljle  in  water,  soluble  in  alcohol,  ether,  and  chloroform.  It  has  no  odor 
when  pure,  but  has  a  slight  burning  taste.  Dose,  0.25  G.  (4  grs.) ;  B.  P.  2 — 
5  grs. 

Pidvi^   AcdaniUdi  Composilm   (U.   S.   P.)   contains  7   parts  of  acetanilidc, 
1  of  carfcine,  and  2  of  sodium  bicarbonate.    Dose,  0.5  G.  (7^  grs.). 
Nonofficial. 

I'l/nnnidon,  small  colorless  crystals  slightly  alkaline  in  reaction,  almost 
tast(•k^ss.  s(jluble  in  11  parts  of  water.  Dose,  0.3-0.4  G.  (5-6  grs.)  in  tablets 
or  i)(nvd(.*r. 

Mdbdcinc,  Ladophcninc,  Thcrmodlne  and  S(d<)i)lHn  all  reseml)le  each  other 
in  being  iM.solublc  in  water,  colorless,  and  crystalline,  and  are  ])rcscril)eil  in 
tlu!  same  way  as  phenacctine  and  in  doses  of  0.5-1  G. 

I'licnoroll  is  gciici-ally  used  as  the  liydrochloratc,  which  is  fairly  soluble  in 
water,  while  SalocoU  is  insoluble.    0.5-1  G.  (S-15  grs.). 


THE  ANTIPYREriCS  481 

M(tlakinc,  SalocoU  and  Sdlophcn  all  bfcak  up  in  the  body,  freeing  sali(;ylic 
acid,  so  that,  in  addition  to  the  antipyretic  action,  the  characteristic  effects 
of  this  acid  may  be  elicited  by  them. 

The  antipyretics  arc  almost  invaria))ly  given  by  the  mouth.  Antipyrine 
has  been  injected  hypodermically,  but  this  is  somewhat  painful,  because  much 
larger  quantities  have  to  be  used  than  are  generally  given  by  this  method, 
and  the  solutions  have,  therefore,  to  be  more  concentrated  (30-50  per  cent.). 

Among  the  members  of  this  group,  phenacetine  is  probably  that  most  witlely 
used  at  the  present  time;  antipjTine  is  also  popular.  Acetanilide  is  much  more 
dangerous  than  these  and  should  be  discarded. 

Therapeutic  Uses. — The  antipyretics  are  used  chiefly  to  Reduce  the 
Fever  Temperature.  The  most  satisfactory  results  are  obtained  from 
those  ^^■llieh  act  somewhat  slowly,  but  which  preserve  a  low  temjiera- 
ture  for  some  time,  and  antipyrine  and  the  phenetidine  compounds 
are  thus  preferable  to  the  earlier  remedies,  which  produce  a  more 
abrupt  fall,  after  which  the  temperature  soon  regains  its  former 
height.  The  best  effects  are  obtained  when  the  antipyretic  is  given 
at  the  commencement  of  a  natural  remission,  the  temperature  often 
falling  2-4  degrees  in  the  course  of  the  next  2-3  hours,  and  only  rising 
slowly  afterward.  In  some  fevers  the  antipyretics  have  much  less 
tendency  to  lower  the  temperature  than  in  others.  Thus  in  septicaemia 
larger  doses  are  required  than  in  typhoid  and  not  infrequently  no 
satisfactory  reduction  of  the  temperature  follows  the  administration 
of  the  maximal  quantity.  Pneumonia  is  also  said  by  some  writers  not 
to  be  afTected  so  easily  as  some  other  febrile  conditions  in  which  the 
heat-regulating  centre  appears  to  be  in  a  less  stable  condition,  as  is 
manifested  by  the  occurrence  of  large  spontaneous  variations  of  tem- 
perature. The  reduction  of  the  temperature  by  the  antipyretics  lasts 
only  as  long  as  the  drug  is  present  in  sufficient  quantity  in  the  body, 
and  accordingly  as  soon  as  sufficient  has  been  excreted,  the  intoxication 
of  the  regulating  mechanism  begins  again,  and  the  temperature  soon 
rises  to  its  former  height.  The  antipyretics  do  not  act  on  the  cause 
of  the  disease,  but  only  remove  one  of  the  symptoms,  but  this  in  itself 
is  not  an  argument  against  their  use,  as  is  apparently  believed  by 
some  writers,  because  as  long  as  the  physician  is  unable  to  treat  the 
cause  directly,  he  is  justified  in  taking  such  measures  as  are  possible 
to  remove  the  symptoms,  rather  than  in  adopting  an  expectant  treat- 
ment, pure  and  simple.  The  extensive  use  of  these  remedies  shows 
\ery  clearly  that  the  high  temperature  is  merely  a  symptom  of  disease, 
and  not  the  disease  itself,  and  the  question  has  been  much  debated 
whether  the  reduction  of  fever  is  in  any  way  beneficial.  No  one  questions 
that  some  antipyretic  measures  should  be  taken  when  the  temperature 
rises  so  high  as  to  form  a  danger  in  itself,  but  their  use  in  ordinary 
fever  cases  is  more  doubtful,  and  many  physicians  deprecate  it  unless 
in  exceptional  conditions.  The  very  large  doses  formerly  used  un- 
doubtedly induced  dangerous  symptoms  occasionally,  but  there  is 
little  risk  of  this  occurring  from  the  intelligent  use  of  the  less  violent 
members  of  the  series.  It  has  recently  been  shown  by  Schutze  and 
Beniasch  that  the  use  of  the  antipyretics  does  not  retard  the  formation 
31 


482  SUBSTANCES  ACTING  AFTER  ABSORPTION 

of  Xhv  protcfthe  substances  (antitoxins)  to  Mhioh  tlie  rcco\  cry  from 
fever  is  attributed,  for  in  infected  animals  treated  with  enormous 
(juantities  of  antipyrinc  the  serum  displayed  the  same  ajjghitinating 
jjroperties  toward  the  baciUi  as  that  of  controls  which  were  not  sub- 
jected to  any  medication. 

A  more  serious  argument  against  their  use  in  fe\'er  is  that  the 
course  of  the  disease  is  less  readily  followed,  because  one  of  the  guid- 
ing symptoms — the  temperature  variations— is  no  longer  dependent 
solely  ui)on  the  severity  of  the  intoxication  with  the  fever  poisons, 
and  both  diagnosis  and  ])rognosis  are  thus  rendered  more  difficult. 
For  example,  in  typhoid  fe^•er  a  sudden  fall  of  temperature  often 
gives  the  first  indication  of  such  a  complication  as  haemorrhage, 
but  if  an  antipyretic  has  been  given  beforehand,  this  indication  may 
be  entirely  absent.  On  the  other  hand,  it  is  urged  in  favor  of  the 
antipyretic  treatment  that  the  patient  feels  more  comfortable  and 
easier  when  the  temperature  is  reduced,  and  that  this  alone  may 
fa^'orably  influence  the  course  of  the  disease.  Besides,  the  high  tem- 
perature in  itself  increases  the  tissue  waste  and  causes  larger  draughts 
on  the  resources  of  the  patient  than  would  be  made  with  the  same 
amount  of  poison  in  the  tissues  at  a  lower  temperature;  and  although 
the  influence  of  the  high  temperature  on  the  metabolism  was  undoubt- 
edly exaggerated  at  one  time,  this  consideration  is  by  no  means  de\oid 
of  weight.  The  theory  that  fever  is  a  defensive  measure  taken  by  the 
organism  against  the  causes  of  disease  and  ought  not  to  be  interfered 
with  therefore,  is  now  seldom  mentioned.  The  antipyretic  treatment 
of  fever  is  of  value,  then,  in  cases  where  the  temperature  is  so  high 
as  to  endanger  life,  in  cases  in  which  the  rise  of  temperature  is  the 
chief  cause  of  distress  and  no  complications  are  to  be  api)rehended, 
and,  in  general,  in  cases  in  which  the  increased  comfort  of  the  i)atient 
is  not  counterbalanced  by  its  obscuring  the  diagnosis  and  prognosis. 
On  the  other  hand,  there  is  no  reason  to  suppose  that  it  lessens  the 
mortality  or  shortens  the  course  of  most  fevers,  or  that  it  prevents 
complications  of  any  kind  exce]>t  excessively  high  temperature,  and 
the  routine  treatment  of  fever  with  antipyretics  is  to  be  deprecated. 

The  chief  rival  of  the  antipyretics  in  the  treatment  of  fever  in  the 
present  day  is  the  so-called  cold-bath  treatment,  in  which  the  fe\er 
l)atient  is  loathed  frequently  in  water  the  temperature  of  which  varies 
from  70  90°  F.  in  different  hosi)itals.  The  temi)erature  generally 
falls  to  a  considerable  extent  under  this  treatment,  and  \ery  often  a 
general  imi)rovement  in  the  symptoms  .occurs.  The  effect  on  the  tem- 
perature is  mainly  due  to  the  abstraction  of  heat  from  the  body,  and 
thus  far  corresponds  to  that  of  the  antipyretics.  In  the  cold-bath 
treatment,  however,  the  loss  of  heat  is  not  immediately  due  to  the 
dilatation  of  the  skin  vessels,  for  baths  at  70°  F.  ha\e  rather  the 
effect  of  constricting  the  vessels  primarily,  whatever  may  be  the  sub- 
sequent ell'ect.  The  heat  outjiut  increases  here  from  the  change  in 
the  external  medium,  and  not  from  any  alteration  in  the  skin  itself. 
'J'he  lall  of  tciiiprraturc  is  generallx    not   so  great  as  under  the  anti- 


II 


THE  ANTIl'VIiETICS  483 

pyretics,  and  tlie  regulation  is  not  directly  affected,  for  the  patient 
shivers  and  becomes  cyanotic  long  before  the  normal  temperature 
is  reached.  The  therapeutic  virtue  of  the  cold  bath  was  formerly 
believed  to  lie  exclusively  in  the  abstraction  of  heat  and  the  fall  of 
temperature,  but  many  advocates  of  the  treatment  now  hold  that  this 
is  of  less  importance  than  the  effects  on  the  circulation  and  the  brain, 
which  are  elicited  reflexly  by  the  cold  water  applied  to  the  skin,  and 
which  are  not  now  believed  to  be  due  to  the  fall  in  temperature. 
Whether  this  view  is  correct  or  not,  the  whole  nature  of  the  fall  in 
temperature  is  different  from  that  produced  by  the.  antipyretics,  and 
the  metabolism,  instead  of  becoming  less  active  as  it  does  under  the 
latter,  rather  tends  to  increase  under  the  cold  baths,  at  least  as  far  as 
the  tissue  change  can  be  measured  by  the  nitrogen  excreted.  The 
relative  therapeutic  value  of  the  two  methods  of  treating  fevers  can 
only  be  determined  by  clinical  experience,  and  the  clinicians  do  not 
appear  to  be  so  enthusiastic  in  their  advocacy  of  the  cold  bath  as  they 
were  a  few  years  ago.  However  the  matter  may  stand  in  hospital 
practice,  in  which  trained  assistance  is  available,  the  antipyretics  have 
a  great  advantage  in  many  cases  in  which  treatment  has  to  be  carried 
out  without  any  such  facilities,  for  the  administration  of  these  drugs 
may,  of  course,  be  entrusted  to  ordinary  persons,  whereas  the  cold 
bath  can  be  gi^•en  only  by  the  physician  himself  or  by  trained  attendants. 
Particularly  in  the  milder  fevers,  where  no  complicated  measures,  such 
as  the  cold  bath,  are  considered  necessary,  the  antipyretics  give  relief 
to  the  patient  by  remo^•ing  the  feeling  of  heat  and  discomfort. 

Other  antipyretic  drugs  are  quinine  and  alcohol,  but  neither  of  these 
produces  an  equal  fall  of  temperature  unless  with  the  presence  of 
alarming  and  dangerous  symptoms.  Quinine  acts  probably  through 
reducing  the  metabolism,  and  alcohol  by  dilating  the  skin  capillaries, 
and  perhaps  by  lessening  the  mo^'ements  and  thereby  the  formation 
of  heat.  Both  of  these  drugs  are  used  very  much  less  as  antipyretics 
now  than  formerly,  as,  besides  their  undesirable  secondary  effects,  the 
fall  of  temperature  is  less  certain  and  less  profound  than  under  the 
modern  antipyretics. 

The  antii)yretics  are  also  used  very  largely  to  relieve  Neuralgic  Pain 
and  Headache,  often  with  complete  successs.  The  analgesic  action  of 
these  bodies  is  apparently  quite  different  from  that  of  morphine,  for 
in  many  instances  in  which  the  latter  is  successful  they  fail  to  alle- 
viate the  condition.  On  the  other  hand  antipyrine  and  its  allies  can 
often  be  used  where  morphine  is  contra-indicated,  either  from  the 
danger  of  the  habit  being  formed,  or  from  the  somnolence  it  induces. 
The  antipyretics  appear  to  be  of  little  or  no  value  in  relie^•ing  the 
pain  caused  by  acute  inflammatory  conditions,  while  on  the  other 
hand  they  are  almost  specific  in  some  neuralgic  cases.  Almost  all  of 
the  antij)yretics  are  efficient  in  these  cases,  but  larger  doses  are  gener- 
ally required  than  to  reduce  fever,  and  the  more  powerful  such  as 
antifebrine,  are  often  preferred  to  the  safer  and  more  slowly  acting 
phenetidines.     Antifebrine  or  acetanilide  has  so  often  given  rise  to 


4S4  SUBSTANCES  ACTINd  AFTER  ABSORPTION 

poison i I !<;•,  li()\vt>\'(T,  that  its  use  for  this  piirj)()se  is  to  be  deprecated, 
especially  as  equally  satisfactory  results  may  be  obtained  from  somewliat 
larger  quantities  of  the  safer  antipyretics.  Acetylsalicylic  acid  has  been 
used  instead  of  the  antipyretic  group  of  late  years.  Caffeine  is  often 
prescribed  along  with  the  antipyretic,  as  in  the  compound  acetanilide 
powder,  but  is  said  to  increase  the  toxicity  of  acetanilide. 

Several  of  the  antipyretics  have  been  used  as  Substitutes  for  Quinine 
in  the  treatment  of  malaria,  but  none  of  them  haNc  the  specific  action 
of  the  latter  on  the  organism  of  malaria,  and,  although  they  may  reduce 
the  temperature,  they  do  not  prevent  the  other  symptoms  and  do  not 
remove  the  cause  of  the  disease.  In  the  same  way  they  do  not  seem 
to  equal  salicylic  acid  in  efficiency  in  acute  rheumatism,  although  here 
again  they  reduce  the  temperature.  Even  those  which  release  salicylate 
in  the  body,  such  as  malakine  and  salophen,  do  not  supply  adequate 
amounts  of  it  for  the  treatment  of  rheumatic  fever,  in  which  the  pure 
salicylate  is  much  to  be  preferred. 

The  antipyretics  are  used  to  a  considerable  extent  in  cases  of  dia- 
betes insipidus  and  mellitus  and  appear  to  relieve  the  discomfort  and 
in  some  cases  to  improve  the  general  condition.  In  whooping-cough 
aiitipyrine  often  lessens  the  severity  of  the  attacks  and  also  renders 
them  less  frequent,  and  is  said  to  shorten  the  course  of  the  disease. 

The  use  of  antipyrine  and  other  members  of  this  series  as  sedatives  in  hj'per- 
acitivity  of  the  motor  functions  of  the  brain,  such  as  epile])sy  and  chorea,  has 
not  been  attended  with  great  success,  although  temporarv  improvement  has 
occasionally  been  noted,  as  after  so  many  other  remedies. 

Antipyrine  and  several  others  of  this  series  have  been  advocated  as  local 
sedatives  or  anfesthetics,  and  have  been  used  occasionally  to  lessen  the  irrita- 
bility of  the  throat  and  larynx  and  thus  to  permit  of  the  minor  manipulations 
of  laryngology.  Holocaine,  a  body  closely  related  to  phenacetine,  has  been  em- 
ployed to  a  limited  extent  as  a  local  anaesthetic  in  ophthalmology  (sec  p.  363). 

The  occurrence  of  collapse  and  other  symptoms  has  led  to  a  con- 
siderable amount  of  distrust  of  the  antipyretics  among  many  of  the 
medical  profession.  In  justice  it  has  to  be  remembered  that  in  many 
cases  these  symptoms  were  produced  only  by  ^'ery  large  doses,  aufl 
that  since  experience  lias  shown  that  beneficial  results  may  be  obtained 
by  smaller  quantities,  these  cases  have  notably  dinunished  in  medical 
[)ractice.  Unfortunately,  this  distrust  is  not  entertained  by  a  large 
class  of  the  laity,  and  inunerous  cases  of  ])oisoning  arise  from  the 
imi)ressi()n  that  the  antipyretics  arc  not  dangerous  drugs.  For  the 
most  part,  jjoisoning  seems  to  be  due  to  a  peculiar  sensitiveness  or 
idiosyncrasy,  which  cannot  be  foreseen,  but  in  cases  of  great  exhaustion 
and  asthenia,  especially  when  accompanied  with  ana?mia,  these  drugs 
h.ave  to  be  used  with  great  care  or  avoidc^l  entirely. 

IJlHI.IOCRAlMlY. 

Sawadowikij.     Ccnfrall)!.  f.  mod.  Wiss.,  1888,  p.  H.^. 

Martin      Thcrap.  Gazette,  xi,  1KS7,  p.  289 

Lcpinc  cl  Porter.     Comptes  rendus,  cvi,  p.  102:5,  and  <vii,  p.   1 1(5 


SALICYLATES  485 

Jaffe  u.  Hubert.     Ztschr.  f.  physiol.  Chcni.,  xii,  p.  295. 

Morner.     Ibid.,  xiii,  p.  12. 

Loewi.     Ergeb.  der  Physiologie,  iii,  1,  p.  365. 

Nencki.     Arch.  f.  exp.  Path.  u.  Pharni.,  xxx,  p.  306. 

V.  Mering.     Therap.  Monats.,  1893,  p.  577. 

Hinsberg  u.  Treupel.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxiii,  p.  216. 

Pellacani.     Arch.  Italien.  de  Biologic,  viii,  p.  76. 

Lepine.     Revue  de  Medicine,  1887,  p.  306. 

Cahn  u.  Hepp.     Beri.  klin.  Woch.,  1887,  p.  4. 

Filehne,  Liebermeister,  etc.     Congress  f.  inn.  Med.,  1885,  pp.  118-185;    1896,  pp.  3-100 

Kumagawa.     Virchows  Arch.,  cxiii,  p.  134. 

Hinsberg  u.  Kast.     Centralbl.  f.  d.  med.  AViss.,  1887,  p.  145.     (Phcnacetine.) 

Maass.     Zts.  f.  khn.  Med.,  xxviii,  p.  139.     (Analgen.) 

Filehne.     Berl.  klin.  Woch.,  1882,  p.  681;    1883,  p.  77. 

Stern.     Zts.  f.  klin.  Med.,  xx,  p.  82. 

Hildcbrandt.     Virchows  Arch.,  cxxi,  p.  1. 

Rictder.     Ibid.,  cxxiii,  p.  118. 

C.  Rosenthal.     Arch.  f.  Anat.  u.  Phys.,  1888,  p.  1. 

W.  Rosenthal.     Ibid.,  1893,  Suppl.,  p.  243. 

Simon  and  Hock.     Johns  Hopkins  Hospital  Bulletin,  1890. 

Maragliano.     Ztschr.  f.  klin.  Med.,  xvii,  p.  291  and  xiv,  p.  309. 

Gottlieb.     Arch.f  .  exp.  Path.,  xxvi,  p.  419  and  xxviii,  p.  167. 

Kraus.     Wien.  klin.  Woch.,  1894.  pp.  229  and  275. 

Riedel.     Zts.  f.  Heilkundc,  xvi,  p.  55. 

Pemoldt.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxvi,  p.  313. 

Liepelt  u.  Stuhlinger.     Ibid.,  xliii,  pp.  151  and  168. 

Tappeiner.     Ibid.,  xxviii,  p.  295,  and  xxx,  p.  231. 

Heinz.     Virchows  Arch.,  cxxii,  p.  112. 

Schutze.     Zeitschr.  f.  Hygiene,  xxxviii,  p.  205. 

Beniasch.     Zeitschr.  f.  kUn.  Med.,  xlv,  p.  51.    ■ 

Lawrow.     Zeitschr.  f.  phys.  Chemie,  xxxii,  p.  111. 

Reithus.     Arch.  f.  exp.  Path.  u.  Pharm.,  xliv,  p.  239. 

Kiliani.     Arch.  Internat.  de  Pharmacodyn,  xx,  p.  333. 

T  e  trahy  dronaphthylamine . 

A  poison  may  be  mentioned  here  which  has  the  property  of  causing  fever 
temperature  and  even  proves  fatal  from  hyperthemia  in  some  cases.  Tetra- 
hydro-  -i-naphthylamine  (C10H11NH2)  raises  the  temperature  by  increasing  the 
lieat  production  through  muscular  movement  and  by  hmiting  the  heat  loss 
through  constriction  of  the  vessels  of  the  skin  and  superficial  tissues.  The 
muscular  movement  arises  from  central  nervous  excitation,  and  is  shown  in 
tremor  and  convulsions  after  large  doses;  the  oxygen  absorption  and  the 
carbonic  acid  production  is  greatly  augmented.  The  constriction  of  the  cuta- 
neous vessels  is  also  mainly  due  to  stimulation  of  the  vasomotor  centre,  though 
there  may  be  some  slight  action  on  the  vessel  walls  also.  The  pupil  is  widely 
dilated  and  the  eyeball  is  protruded,  from  stimulation  of  the  sympathetic 
mechanism,  partly  in  the  periphery  but  mainly  in  the  central  nervous  system. 
Cacoinc  has  a  similar  but  weaker  action;  the  naphthylamine  compounds  do  not 
cause  local  ansesthesia. 

Stern.     Virchow's  Archiv,  cxv,  p.  34,  ahd  cxxi,  p.  376. 

Jonesen.     Arch.  f.  Exp.  Path.,  Ix,  p.  345. 

Elliott.     Jour,  of  Physiol.,  xliv,  p.  382. 

Mutch  and  Pembrey.     Ibid.,  xliii,  p.  109. 

Cloetta  u.  Waser.     Arch.  f.  Exp.  Path,,  Ixxiii,  pp.  358,  436. 

XXXn.    SALICYLATES. 

Salicylic  Acid,  CeHjOTTCOOH,  was  introduced  into  medical  use  as  a 
substitute  for  carbolic  acid,  but  toj^a'ther  witli  its  salts  has  proved  to 


486  SUBSTANCES  ACTING  AFTER  ABSORPTION 

have  a  specific  action  in  acute  rheumatism;  sodium  saHcylatc  has  ahiiost 
entirely  displaced  the  acid  in  the  treatment  of  this  disease.  Some  of 
the  esters  have  also  been  employed;  mcfhyl  mUcijJatc,  C6ll4()HCO()CIl3, 
which  is  found  in  the  volatile  oil  obtained  from  the  wintcrgrccn  (Gaul- 
theria  ])rocunibcns)  and  from  birch  })ark  (Betula  lenta)  and  which  is 
also  formed  synthetically;  phenyl  salicylate  or  salul,  C6H4OIICOOC6  H5, 
formed  synthetically;  the  numerous  other  salicylic  esters  which  have 
been  introduced  by  enterprising  manufacturers  have  not  attained 
a  wide  use.  A  recently  introduced  compound  which  has  been  largely 
employed  is  acetyl-salicylic  acid,  C6n40COCH3.COOH,  or  as^tirin. 
Salicin,  C13H18O7,  is  a  glucoside  found  in  the  poplars  and  willows,  which 
forms  salicylate  in  the  body  and  has  had  a  limited  use. 

Local  Action. — The  salicylates  have  some  antiseptic  action,  which  is 
much  smaller,  however,  in  the  case  of  the  neutral  salts  than  in  the  acid, 
in  w'hich  the  specific  action  of  the  salicylate  radicle  is  reinforced  by  the 
acid  ion.  Thus  the  putrefaction  of  protein  solutions  and  the  alcoholic 
and  acetic  acid  fermentations  are  retarded,  or  entirely  prevented 
by  the  presence  of  comparatively'  small  quantities  of  salicyHc  acid  or 
of  the  salicylates.  They  offer  some  points  of  contrast  with  carbolic 
acid,  however,  for  it  is  found  that  if  much  protein  is  present  the 
salicylic  preparations  are  generally  less  efficient  than  phenol;  this  is 
perhaps  due  to  the  phenol  being  ^'olatile  and  therefore  penetrating 
more  readily  and  forming  less  stable  combinations  with  the  protein. 
Salicylic  acid,  on  the  other  hand,  does  not  evaporate  and  therefore 
preserves  bodies  which  are  exposed  to  the  air  for  a  longer  time  than 
carbolic  acid,  which  is  soon  dissipated.  These  considerations  may 
perhaps  explain  the  very  different  results  which  have  been  obtained 
by  different  observers  in  regard  to  the  comparative  germicidal  power 
of  these  substances.  The  movements  of  plant  protoplasm,  protozoa 
and  leucocytes  are  prevented  by  salicylic  acid  as  by  quinine  and  the 
other  aromatic  antiseptics.  Salicylic  acid  retards  the  digestion  of 
proteins  by  the  gastric  and  pancreatic  juices,  and  the  decomposition 
of  glucosides  by  ferments,  but  this  is  probably  due  to  its  acidity  and  not 
to  the  salicylate  ion. 

Irritant  Action. — When  salicylic  acid  is  applied  for  some  time  as  a 
powder  to  A\ounds,  mucous  membranes,  or  e\en  the  skin,  it  may  induce 
corrosion  and  necrosis.  It  sometimes  causes  soreness  and  irritation  of 
the  mouth  and  throat  when  swallowed  in  powder,  and  congestion  and 
even  erosion  of  the  mucous  membrane  of  the  stomach  ha\e  been  ob- 
served; even  dilute  solutions  often  cause  pain  and  discomfort  in  the 
stomach.  Sodium  salicylate  is  only  very  slightly  irritant,  but  when 
it  is  swallowed,  some  of  the  acid  is  disengaged  by  the  hydrochloric  acid 
of  the  stomach  and  may  be  deposited  on  the  mucous  membrane  and 
gi\e  rise  to  acute  dyspepsia. 

Symptoms.  -Salicylic  acid  and  its  salts  are  rapidly  absorbed  from 
the  stomach  and  intestine  and  as  a  general  rule  ])ro(luce  no  syin])toms, 
unless  \\\\v\\  gi\('n  in  very  large  doses.  Sonic  indix  iduals,  however, 
arc  |)C(iiliarly  scnsitiNc  to  the  action  of  the  salicylates,  and    in    these 


SALICYLATES  487 

comparatively  small  doses  are  followed  by  symptoms^  which  are  gen- 
erally of  only  slight  imi)ortance,  but  which  are  sometimes  sufficiently 
grave  to  cause  anxiety,  and  in  \ery  rare  cases  ha\'e  been  followed  by 
death. 

The  ordinary  symptoms  are  a  feeling  of  heaviness  and  fulness  m 
the  head,  with  hissing  or  roaring  sounds  in  the  ears  exactly  resem- 
bling those  produced  by  quinine.  These  may  be  followed  by  some 
confusion  and  dulness  and  by  indistinct  sight  and  hearing.  Very 
often  the  patient  complains  of  excessive  perspiration  and  a  sense  of 
warmth  all  over  the  body.  Dyspnoea,  marked  by  exceedingly  deep 
and  labored  respiration,  has  been  noted  in  more  serious  cases  of  poi- 
soning, and  a  condition  of  collapse  with  slow,  weak  pulse,  subnormal 
temperature  and  partial  or  complete  unconsciousness  may  follow.  In 
others  delirium  and  hallucinations  of  sight  and  hearing  have  occurred, 
these  being  more  frequently  seen  in  chronic  alcoholic  patients  and  in 
cases  of  diabetes  than  under  other  conditions.  Albumin,  casts  and 
even  hsemoglobin  and  blood  in  the  urine  have  been  noted  as  sequelae. 
Various  forms  of  skin  eruptions  have  been  described  as  occurring 
under  the  use  of  salicylic  acid,  sometimes  after  a  single  dose,  but 
much  more  frequently  aft^r  prolonged  treatment.  They  resemble 
those  seen  under  the  antipyretics,  but  seem  to  be  less  frequently  elic- 
ited, by  salicylic  acid.  Abortion  has  been  repeatedlv'  observed  under 
salicylate  treatment,  but  it  seems  open  to  question  whether  this  was 
due  to  the  remedy  or  to  the  disease.  Haemorrhages  from  the  uterus, 
nose,  mouth  and  intestine  have  also  been  credited  to  the  action  of  this 
drug.  Numerous  other  symptoms  have  been  noted  after  it,  but  so 
rarely  that  a  doubt  may  be  entertained  as  to  whether  they  were  not  due 
to  some  special  condition,  or  perhaps  to  some  impurity  in  the  drug. 

In  animals  salicylates  injected  intravenously  cause  some  acceleration 
of  the  pulse  and  respiration,  followed  by  slowness  and  weakness  of 
the  heart,  and  often  by  marked  dyspnoea.  Depression  of  the  central 
nervous  system  is  shown  by  slowness,  weakness  and  incoordination  of 
the  spontaneous  movements,  and  eventually  by  stupor  and  arrest 
of  the  respiration,  which  is  generally  preceded  by  convulsions.  Photo- 
phobia and  clonic  spasms  have  been  observed  in  some  dogs.  Hyper- 
semia  of  the  kidney,  liver,  brain  and  tympanum  are  sometimes  found 
at  the  autopsy  on  dogs  poisoned  with  salicylic  acid,  and  when  the  drug 
has  been  given  in  powder,  congestion,  irritation,  and  necrosis  of  the 
gastric  mucous  membrane.  This  irritation  of  the  stomach  often  causes 
vomiting  in  dogs,  and  the  poison  being  thus  eliminated,  no  further 
symptoms  appear.  Vomiting  occurs  in  cats  when  salicylate  is  injected 
hypodermically,  which  indicates  some  action  on  the  medullary  centres; 
increased  reflexes,  tremors  and  restlessness  are  also  described  in  these 
animals  in  which  a  more  distinct  stimulation  of  the  central  ner\ous 
system  seems  to  be  elicited  than  in  man. 

In  the  frog  salicylic  acid  produces  quickened  respiration  and  in- 
creased reflexes,  followed  by  depression  of  the  si^ontaneous  mo\ements, 
tremor,  and  clonic  contractions.    The  heart  is  slow,  dilateil,  and  weak. 


4SS  SUBSTANCES  ACTING  AFTER  ABSORPTION 

Tlie  symptoms  elicited  by  salicylic  acid  and  its  salts  are  therefore 
\ery  iiid'efiiiite,  and  with  few  exceptions  occur  so  seldom  in  man  that 
they  may  hv  discussed  very  shortly. 

The  Disorders  of  Hearing  ha\e  been  ascribed  to  conjjestion  of  the 
tympanum,  but  may  perhaps  indicate  some  changes  in  the  nerve  cells 
of  the  ear  analogous  to  those  observed  under  quinine.  As  a  general 
rule  they  pass  off  in  the  course  of  a  few  hours  or  days,  but  they  some- 
times leave  a  more  or  less  permanent  impairment  of  the  sense  of  hear- 
ing. The  Dimness  of  Sight,  sometimes  amounting  to  complete  blind- 
ness, is  due  to  vascular  or  retinal  changes  in  the  eye  (see  Quinine), 
and  some  disturbance  of  the  circulation  of  the  brain  and  head  may  be 
the  cause  of  the  dulness  and  fulness  of  the  head  comi)lained  of,  and 
of  the  not  infrequent  epistaxis.  ]\laragliano  showed  by  plethysmo- 
grai)hic  measurements  that  the  Vessels  of  the  Skin  are  dilated  by  sali- 
cylic acid  in  the  same  way  as  by  the  antipyretics.  The  exact  mechanism 
by  which  these  alterations  in  the  distribution  of  the  blood  are  pro- 
ducetl,  is  unknown,  but  the  most  probable  exi)lanation  Mould  seem  to 
be  that  the  vaso-dilator  centres  in  the  medulla  controlling  these  areas 
are  excited. 

The  general  Blood-Pressure  is  found  to  be  increased  by  small  quan- 
tities of  the  salicylates  from  stimulation  of  the  vaso-constrictor  centre, 
while  after  very  large  injections  into  the  bloodvessels,  the  pressure 
is  lowered,  partly  perhaps  from  depression  of  the  centre,  but  mainly 
from  the  cardiac  action  of  the  drug 

Small  quantities  are  found  to  accelerate  the  Heart  in  animals  in  the 
same  way  as  small  doses  of  the  other  aromatic  bodies,  apparently 
from  direct  action  on  the  cardiac  muscle.  Very  large  doses  produce 
a  slow,  weak  and  dilated  heart,  and  a  corresponding  fall  in  the  blood- 
pressure. 

The  acceleration  of  the  Respiration  and  the  dyspncra  which  ha\-e 
been  noted  occasionally  in  man,  seem  to  be  due  to  some  central  action. 
In  animals  the  respiration  is  first  accelerated  to  some  extent,  and  then 
slowed,  apparently  from  the  respiratory  centre  being  first  excited 
and  then  dei)ressed,  and  eventually  paralyzed  by  very  large  quan- 
tities of  the  drug.  Death  seems  to  be  due  to  this  paralysis,  the  heart 
continuing  to  beat  for  some  time  afterward. 

The  effects  of  salicylic  acid  on  the  Central  Nervous  System  seem  to 
be  comparatively  slight,  except  in  cases  in  which  a  si)ecial  idiosyn- 
crasy exists.  No  such  convulsive  action  as  occurs  under  others  of  the 
aronuitic  series  has  been  observed  under  it,  and  in  animals  there  seems 
no  marked  depression  save  in  the  medulla  oblongata.  The  convul- 
sions which  are  observed  before  death  are  i)robably  not  due  to  the 
ilirect  action  of  the  drug,  but  to  the  asi)iiyxia.  In  the  medulla  oblon- 
gata the  respiratory  and  vaso-constrictor  centres,  and  probably  the 
\aso-dilator,  seem  to  be  first  stinnilated  and  then  depressed. 

The  Perspiration  which  so  often  follows  the  administration  of  sali- 
cyhc  preparations  may  be  due  in  i)art  to  the  dilatation  of  the  skin  ves- 
sels, but  is  probably  to  l>e  ascribed  rather  to  increased  actixity  of  th<> 


SAIJCYLATES  489 

sweat  centres.  Some  of  the  Skin  Rashes  nui\'  also  he  caused  hy  tlie 
dihitation  of  the  cutaneous  vessels,  and  perhaps  in  all  cases  this  may 
be  looked  upon  as  a  fa\orable  condition,  which  leads  to  eruptions  in 
individuals  who  are  predisposed  to  them. 

Salicylic  acid  and  its  salts  increase  to  some  extent  the  Secretion  of 
the  Urine,  probably  through  a  direct  action  on  the  renal  epithelium, 
although  the  increased  formation  of  urea  may  also  play  a  part  in  the 
slight  diuresis.  Irritation  of  the  kidney  and  nephritis  are  observed 
in  some  cases,  with  the  appearance  of  albumin  and  blood  in  the  urine. 

The  salicylic  preparations  produce  a  slightly  augmented  flow  of 
Bile,  apparently  from  some  specific  action  on  the  liver  cells.  The  bile 
is  generally  more  dilute  than  normal,  the  fluid  increasing  more  than 
the  solids,  though  the  total  solid  excreted  is  augmented. 

Salicylate  has  been  said  to  lower  the  normal  Temperature,  but  this 
seems  to  be  erroneous,  except  when  very  large  quantities  produce 
a  condition  akin  to  collapse.  In  fever  patients,  however,  it  often 
causes  a  marked  fall  of  temperature,  and  it  was  formerly  used  as  an 
antipyretic  for  this  reason.  The  action  is  probably  explained  by  the 
dilatation  of  the  cutaneous  vessels  and  the  increase  in  the  output  of 
heat.  (See  Antipyretics.)  Dilatation  of  the  skin  vessels  also  occurs  in 
normal  persons  after  salicylates,  but  this  is  probably  counterbalanced 
in  them  by  increased  heat  formation.  The  fall  in  temperature  after 
salicylic  acid  is  generally  less  in  extent  and  of  shorter  duration  than 
that  following  the  members  of  the  antipyrine  series. 

In  its  passage  through  the  tissues,  salicylic  acid  modifies  the  Meta- 
bolism, as  is  shown  by  an  increase  of  10-12  per  cent,  in  the  nitrogen 
and  sulphur  of  the  urine.  This  indicates  a  considerably  augmented 
decomposition  of  the  proteins  of  the  body,  but  whether  it  is  accom- 
panied by  increased  oxidation  is  unknown.  A  still  more  notable  aug- 
mentation of  the  uric  acid  excreted  has  been  observed,  different  authors 
estimating  it  at  30-45  and  even  100  per  cent.  This  occurs  also  in 
animals  and  persons  on  a  purine-free  diet;  a  similar  action  has  been 
described  under  atophan  (p.  443). 

Salicylate  circulates  in  the  blood  as  the  sodium  salt,  and  is  said  to 
accumulate  in  large  quantities  in  the  cavities  of  the  Joints,  being  taken 
up  from  the  blood  by  the  syno\ial  membranes  and  secreted  into  the 
synovial  fluids;  this  has  been  supposed  to  explain  its  action  in  acute 
rheumatism,  but  has  not  been  confirmed.  It  is  Excreted  by  the  kidneys, 
for  the  most  part  in  a  combination  with  glycine,  which  is  known  as 
salicyluric  acid,  and  which  is  strictly  analogous  to  hippuric  acid.  Sali- 
cyluric acid  seems  practically  inert,  and  has  no  eft'ect  in  acute  rhemna- 
tism.  Some  of  the  salicylic  acid  is  excreted  uncombined.  It  appears 
in  the  urine  within  an  hour  of  its  administration  by  the  mouth  and  is 
all  eliminated  in  48  hours.  It  has  also  been  found  in  the  milk,  per- 
spiration and  bile,  but  does  not  appear  to  be  excreted  into  the  stomach. 

Methyl  Salicylate  has  a  hot,  burning  taste,  and  like  other  volatile 
oils  produces  a  feeling  of  warmth  in  the  stomach.  In  many  cases  it  is 
well  borne,  but  some  patients  complain  of  pain  in  the  stomach,  loss  of 


490  SUBSTANCES  ACTING  AFTER  ABSORPTION 

appetite,  and  even  nausea  and  vomiting.  Much  of  it  is  decomposed 
to  salicylate  in  the  intestine  and  this  is  rapidly  absorbed  and  produces 
the  characteristic  symptoms  of  salicylic  acid  in  large  doses. 

Salicin,  a  glucoside  found  in  many  species  of  willow  and  poplar,  is 
decomposed  into  salicylic  alcohol,  which  is  oxidized  to  salicylates 
in  the  body.  It  is  probable  that  the  decomposition,  like  that  of  the 
ordinary  esters,  takes  place  chiefly  in  the  intestine,  for  when  it  is  injected 
intravenously  it  is  excreted  unchanged.  It  is  very  bitter,  but  does  not 
irritate  the  mucous  membranes,  and  is  not  so  certain  in  its  action  as 
salicylate.  When  administered  by  the  mouth  it  is  excreted  in  the 
urine  partly  as  salicin,  ])artly  as  saligenin  or  salicyl  alcohol,  and  j)artly 
as  salicylic  and  salicyluric  acids.  - 

Acetylsalicylic  Acid,  or  Aspirin,  passes  through  the  stomach  unchanged 
and  is  free  from  the  gastric  effects  of  salicylic  acid  and  the  salicylates. 
It  is  partially  decomposed  into  salicylic  acid  in  the  bowel,  but  some  of 
it  appears  to  be  absorbed  in  its  original  form.  The  salicylic  acid  formed 
from  it  exercises  its  usual  action  in  the  tissues,  but  there  is  a  further 
action  resembling  that  of  the  antipyretics  in  headache  and  neuralgia, 
and  this  is  attributed  to  the  action  of  the  acetylsalicylate  which  has 
escaped  decomposition  and  has  been  absorbed. 

Salicylic  acid  is  ortho-oxybenzoic  acid,  and  there  are  two  isomers,  metaoxy- 
benzuic  and  paraoxybenzoic  acid,  which  differ  from  it  structurally  only  in  the 
relative  position  of  the  hydroxy!  and  carboxyl  side  chains.  Yet  their  salts  are 
devoid  of  action  in  acute  rheumatism  and  are  not  employed  in  therapeutics.^ 

The  three  isomeric  cresofmic  acids  (CeHs.CHa.OH.COOH)  that  correspond  to 
sahcylic  acid  in  the  position  of  their  hydroxyl  and  carboxyl  groups,  resemble  it 
in  action  and  are  effective  in  acute  rheumatism;  they  are  approximately  equal 
to  sahcyhc  acid  in  toxicity,  but  orthocresotinic  acid  has  a  more  depressant  action 
on  the  heart,  and  as  they  offer  no  advantages  over  salicylates,  they  have  only 
been  used  experimentally  in  therapeutics. 

Preparations. 

AciDUM  Salic YLicuM  (U".  S.  P.,  B.  P.),  salicylic  acid  (C6H4OHCOOH), 
small,  white,  needle-like  crystals,  or  a  light  crystalline  powder,  odorless  with 
a  sweetish,  afterward  acrid,  burning  taste,  slightly  soluble  in  water,  very 
soluble  in  alcohol  or  other.  A  reddish  tinge  indicates  the  presence  of  car- 
bolic acid  or  other  impurities,  and  salicylic  acid  for  internal  use  ought  to  be 
entirely  colorless.'-  It  is  generally  given  in  capsules  or  tablets.  0")  G.  (7^ 
grs.);   13.P.,5-20grs. 

Unguentum  Acidi  Salicylici  (B.  P.),  2  per  cent. 

SoDii  Salicylas  (U.  S.  p.,  B.  P.),  sodium  salicylate  (C6H40HCOONa),  a 
white,  odorless  powder  with  a  sweetish  taste,  very  soluble  in  water,  less  so 
in  alcohol.  1  G.  (15  grs.);  B.  P.,  10-30  grs.  in  capsules  or  tablets,  or  dissolved 
in  syrup. 

'  This  difTercnce  in  activity  between  the  stereoisomers  of  the  benzene  series  is  very  fre- 
quently met,  and  the  relative  toxicity  dififers  in  the  different  compounds;  thus  the  ortho- 
compound  is  most  active  in  the  oxybenzoic  acids  (salicylic  acid),  while  among  the  cresols 
the  metacnsol  is  said  to  be  the  most  poisonous,  and  parachlorphenol  is  more  antiseptic 
than  either  of  its  isomers. 

=  Salicylic  acid  formed  synthetically  from  phenol  is  often  said  to  be  more  poisonous 
than  that  obtained  from  the  oil  of  wintergreen  (methyl  salicylate),  but  this  is  not 
(•(jrri'ct. 


SALICYLATES  491 

Oleum  Gmdthcrice  (U.  S.  P.,  B.  P.),  oil  of  vviutergreen,  a  colorless  or  yellowish 
fluid  with  a  characteristic,  pleasant  odor  and  a  sweetish,  aromatic  tatc,  insol- 
uble in  water,  soluble  in  alcohol,  contains-OO  per  cent,  of  methyl  salicylate. 
1  c.c.  (15  niins.)  in  emulsion  or  capsules;  li.  P.  5-15  mins. 

Olcuin  BeluUv  (U.  S.  P.),  oil  of  sweet  birch,  and 

Mdhylis  Salicylas  (U.  S.  P.,  li.  P.),  artificial  oil  of  wintergreen  (C6H4- 
OHCOUCH3),  are  practically  identical,  and  may  be  prescribed  in  the  same 
doses  and  forms  as  the  oil  of  wintergreen. 

Spiritus  Gaultherice  (U.  S.  P.),  is  used  as  a  flavor  chiefly.    2  c.c.  (30  mins.). 

Salicinum  (U.  S.  P.,  B.  P.),  salicin  (C6H„060C6H4CH20H),  a  glucoside 
obtained  from  several  species  of  willow  and  poplar,  consists  of  white,  silky, 
crystalline  needles,  with  a  very  bitter  taste,  soluble  in  28  parts  of  water.  1  G. 
(15  grs.);  B.  P.,  5-20  grs.,  or  more  every  3  or  4  hours,  given  in  powder,  capsules 
or  in  solution,  which,  however,  is  very  bitter. 

Acidum  Acetijlsalicylicum  (B.  P.),  Aspirin  (C2H3O— OC6H4COOH)  is  com- 
posed of  small  colorless  crystals,  without  odor,  and  is  very  slightly  soluble  in 
water  with  a  more  pleasant  acid  taste  than  salicylic  acid.  It  has  appeared 
under  numerous  designations  of  late  years  and  much  exaggerated  claims  have 
been  made  for  it  as  a  remedy  for  most  diverse  conditions.  Dose,  0.3-1  G. 
(5-15  grs.). 

Therapeutic  Uses. — The  chief  sphere  of  usefulness  of  salicylate  at  the 
present  time  is  in  the  treatment  of  acute  rheumatic  fever,  in  which 
it  seems  to  have  a  specific  action  only  excelled  by  that  of  quinine  in 
malaria.  Some  other  members  of  the  aromatic  series  are  useful  in 
this  condition,  but  none  are  superior  to  the  salicylic  preparations  in 
efficacy.  Under  this  treatment  the  pain  and  swelling  in  the  joints 
rapidly  lessen,  the  temperature  often  falls,  and  the  course  of  the  disease 
is  shortened.  It  is  still  debated  whether  the  salicylic  treatment  reduces 
the  liability  to  endocarditis  and  pericarditis,  which  are  common  com- 
plications of  acute  rheumatic  fever;  some  clinicians  even  state  that  it 
increases  the  risk  of  these  complications,  while  others  advise  the  dis- 
continuance of  the  treatment  when  any  symptoms  arise  from  the  heart. 
The  view  more  generally  entertained,  however,  is  that  the  cardiac 
affections  are  less  often  met  with  and  are  less  severe  under  salicylic 
treatment,  and  very  often  it  is  continued  in  small  quantities  even  after 
the  heart  is  undoubtedly  involved  in  the  disease.  The  remedy  some- 
times fails  in  rheumatism,  as  quinine  does  in  malaria,  and  it  sometimes 
acts  more  satisfactorily  in  one  joint  than  in  another.  Relapses  occur 
even  during  the  continuous  treatment  with  ordinarily  adequate  quan- 
tities of  salicylate,  and  it  is  found  advisable  to  keep  the  patient  under 
observation  as  long  as  was  necessary  before  the  salicylate  treatment 
was  introduced.  (Miller.)  Large  doses  (1-2  G.  or  15-30  grs.)  repeated 
every  2-3  hours  are  necessary  in  some  cases  at  first,  the  quantity  being 
reduced  as  the  symptoms  abate.  Salicylic  acid  is  now  seldom  given, 
sodium  salicylate  having  supplanted  it.  Alkaline  carbonates  are  fre- 
quently recommended  along  with  the  salicylate,  on  the  ground  that 
they  lessen  the  gastric  action  by  preventing  the  formation  of  the 
irritant  salicylic  acid.  Oil  of  wintergreen  may  also  be  used  here,  but, 
like  salicylic  acid,  is  more  liable  to  cause  gastric  irritation.  When  high 
fever  is  present,  the  antipyretic  combinations  of  salicylic  acid,  such  as 
malakine,  may  be  used  with  advantage.     Salicin  is  less  disturbing  to 


402 


SUBSTANCES  ACTING  AFTER  ABSORPTION 


the  stoinacli  than    the    other   preparations,  but  is  less  certain  in  its- 
I'tVeets  and  has  to  be  given  in  hirjjer  quantities. 

In  other  acute  constitutional  diseases  accompanied  by  fever,  sali- 
cylate has  no  such  specific  action  as  in  acute  rheumatic  fever;  this 
suggests  that  in  the  latter  it  acts  on  the  cause  of  this  malady  with 
especial  power,  or  perhaps  that  it  is  put  in  a  favoral)le  position  by 
being  secreted  into  the  joints  which  are  the  seat  of  the  infection. 

Salicxlic  acid  has  also  been  used  in  the  various  forms  of  disease  which 
are  roiighl.N-  classified  as  rheumatic — chronic  rheumatism,  arthritis, 
neuralgia,  myalgia— but  the  ell'ects  are  less  satisfactory  than  in  acute 
rheumatism. 

Fig.  GG 


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Ul 

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SALICYLATE 
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RESP. 

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20     18 

1 

20     22     23     20     20      18  l  20                             | 

C'linioal  rhiirt  of  cases  of  lu-Axie  rheumatic  fever  treated  with  salicylate  of  sodium.      Case 
1,  20  grains  every  four  hours;   Case  2,  20  grains  every  two  hours.      (Stockman.) 

Salicylic  acid  in  some  cases  promotes  the  absorption  of  ettusions 
into  the  serous  membranes,  such  as  the  pleura,  and  also  subretinal 
effusion.  It  is  unknown  how  this  is  effected,  but  it  scarcely  seems 
probable  that  the  slight  diuretic  action  of  the  drug  is  sufficient  to 
account  for  it. 

The  cholagogue  action  of  the  salicylates  is  quite  inconsiderable  in 
comparison  with  that  of  the  bile  itself,  and  in  any  case  in  which  an 
increase  of  the  bile  secretion  is  desirable,  recourse  should  be  had 
rather  to  the  latter.  It  has  recently  been  suggested  by  Knlm  that  the 
salicylic  salts  excreted  in  the  bile  may  retard  the  growth  of  nnerob(>s 
and  thus  i)rove  of  value  in  the  treatment  of  livtT  and  gall-bladder 
infections. 

Salicylic  acid  and  the  salicylate  of  soda  were  at  one  time  w^*:^  to  a 
considerable  extent  as  aiitisejjties  in  surgery,  and  indeed  i)ronnsed  to 
sup])lant  carbolic  acid  for  this  puri)ose,  as  they  were  less  irritating  and 
also  less  y)oisonous.  'Phey  have  been  less  used  of  late  years,  and  although 
bacteriological  exi)erinicnt  has  shown  that  the  acid  is  at  least  as  destruc- 


SALICYLATES  493 

tive  to  the  pyogenic  organisms  as  carl)olie  acid,  most  surgeons  find  it 
less  satisfactory  in  practice.^ 

Salicylic  acid  is  occasionally  applied  locally  in  excessive  sweating, 
and  has  also  been  used  in  \arious  skin  affections  in  which  it  is  desirable 
to  soften  or  partially  dissolve  the  epidermis.  Both  acids  and  salts  are 
absorbed  too  rapidly  to  act  as  intestinal  disinfectants. 

In  1S75  it  was  found  to  have  antipyretic  properties,  and  for  a  few 
years  it  was  used  as  a  general  antipyretic  in  fever,  but  has  been  entirely 
supplanted  for  this  purpose  by  the  more  recently  discovered  antipyrine 
series.  It  was  also  suggested  as  a  substitute  for  quinine,  but  has  no 
specific  action  on  the  malarial  organisms. 

Salicin  is  used  as  a  substitute  for  salicylic  acid  only  in  rheumatic 
fever.    It  has  been  prescribed  as  a  stomachic  bitter. 

Acetylsalicylic  acid  is  used  chiefly  to  relieve  headache  and  neuralgia 
in  the  same  way  as  the  antipyretic  group,  and  for  this  purpose  may 
be  gi^'en  in  doses  of  5  grains. 

Salicylic  preparations  have  to  be  used  with  care  where  any  symp- 
toms of  renal  irritation  are  present.  In  cases  of  poisoning,  the  treat- 
ment is  determined  entirely  by  the  symptoms,  and  no  antidote  is 
known.  Glycine  has  beeen  suggested  for  the  same  reason  as  the  sul- 
phates in  phenol  poisoning,  but  would  presumably  be  of  no  greater 
value. 

Methyl  salicylate,  or  oil  of  wintergreen,  is  often  applied  locally  in 
muscular  and  articular  rheumatism,  it  being  supposed  that  larger 
quantities  thus  reach  the  focus  of  disease  than  when  the  drug  is  taken 
by  the  mouth.  Absorption  certainly  occurs  through  the  skin,  as  is 
proved  by  the  appearance  of  salicyluric  acid  in  the  urine.  But  irrita- 
tion of  the  skin  is  liable  to  be  excited,  and  the  value  of  the  salicylates 
is  doubtful  in  these  diseases.  Mesotan,  or  methoxymethylsalicylate, 
has  been  introduced  as  a  substitute  for  oil  of  wintergreen  in  external 
treatment,  but  has  no  advantages  of  any  consequence  over  the  older 
drug. 

Bibliography. 

Kolbe.     Journ.  f.  pract.  Choinie,  x,  p.  89;    xi,  p.  9;    xii,  p.   161. 
Quincke.     Berl.  klin.  Woch.,  1882,  p.  709. 

Charleris  and  McLennan.     Brit.  Med.  Journ.,  1889,  ii,  p.  1208. 

Stockman.  Brit.  Med.  Journ.,  Nov.  24,  1906;  Edinburgh  Med.  Journ.,  Aug.,  Sept., 
1906;    Journ.  of  Pharmacology,  iv,  p.  97. 

Maragliano.     Zts.  f.  klin.  Med.,  xvii,  p.  291  and  xiv,  p.  309. 

Gottlieb.     Arch.  f.  exp.  Path.,  xxvi,  p.  436. 

Baumann.     Zts.  f.  phys.  Chem.,  i,  p.  253. 

Binz.     Arch.  f.  exp.  Path.  u.  Pharm.,  vii,  p.  280  and  x,  p.  147. 

Luthje.     Deutsch.  Arch.  f.  khn.  Med.,  Ixxiv,  p.  163. 

Kleineberger  and  Oxenius.     Ibid.,  Ixxx,  p.  225. 

Kuhn.     Miinchener  med.  Woch.,  1904,  p.  1457. 

Nencki.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxvi,  p.  401. 

1  Salicylic  acid  has  been  used  very  largely  as  a  preservative  in  wine  and  beer.  No 
evil  effects  have  l>een  definitely  shown  to  follow  the  prolonged  use  of  liquors  thus  treated, 
but  they  may  tend  to  dis  urb  the  digestion,  and  several  governments  have  found  it  advis- 
able to  prohibit  its  use  for  this  purpose. 


494  SUliSTANCES   ACTISC   M'TER   AJSSOh'I'TlON 

Bochrfonlainc.  Comptcs  rendus  d.  1.  Soc.  de  Biol.,  18.S4,  p  412;  Cornptes  rendus 
dc   rAcadtniic,   Ixxxv,   p.   574;    Ixxxvii,   p.   657. 

Mosso.     Arch.  f.  cxp.  Path.  u.  Pharm.,  xxvi,  p.  267. 

C.  Virchow.     Zts.  f.  physiol.  Chem.,  vi,  p.  78. 

Pfaff.     Jour,  of  Exp.  Med.,  ii,  p.  49.  . 

Bondi  u.  Jacoby.     Hofmeister's  Beitr.  zur  chem.  Phys.,  vii,  p.  514. 

Schreiber  u.  Zandy.     Deutsch.  Arch.  f.  klin.  Med.,  Ixii,  p.  242. 

Goodbody.     Jouni.  of  Physiol.,  xxv,  p.  399. 

Ulrici.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlvi,  p.  321. 

Waddcll.     Arch,  Intern.  Med.,  1911,  viii.  p.  748. 

Pelrowa.     Zcitschr.  f.  physiol.  Chem.,  Ixxiv,  p.  429. 

Marine.     Gottingen.  Nachricht.,  1878,  p.  229. 

Maclagan.     Lancet,  1876,  i,  p.  342. 

Senator.     Berl.  klin.  Woch.,  1877,  p.  181. 

Dreser.     Pfliiger's  Archiv,  lxx\a,  p.  306. 

Singer.     Ibid.,  Ixxxiv,  p.  527. 

Gazert.     Deutsch.  Arch.  f.  klin.  Med.,  Ixviii,  p.  142. 

Miller.     Jour.  Amer.  Med.  Assoc,  1914,  ii,  p.  1107. 

XXXin.     TOXINS  AND  ANTITOXINS. 

The  toxins,  are  a  series  of  poisons  whose  existence  has  been  recojj;- 
nized  only  in  recent  years  and  whose  character  is  still  obscure,  but 
they  i^lay  an  ever  increasing  part  in  medicine.  They  are  found  in 
animals  and  in  some  of  the  higher  plants,  and  ha\e  pro\'ed  to  be  the 
means  by  which  many  of  the  pathogenic  mico-organisms  act  in  the 
tissues.  Their  chemid'al  characters  are  still  disputed,  and  none  of 
them  have  been  isolated  in  an  absolutely  pure  form,  as  no  means  has 
yet  been  found  to  separate  them  from  the  proteins  of  the  cells  in  which 
they  are  produced.  jNIany  observers  are  disposed  to  regard  them  as  of 
protein  character,  while  others  believe  that  they  are  of  simpler  com- 
l)osition  and  merely  attached  by  physical  or  loose  chemical  bonds  to 
the  ])r()teins  which  accompany  them. 

These  toxins  are  amongst  the  most  powerful  poisons  known,  but 
\vhen  animals  are  treated  with  small  and  gradually  increasing  doses, 
they  become  insusceptible  to  amounts  that  would  prove  fatal  to  an 
untreated  control  animal,  and  finally  withstand  in  some  instances 
many  hundred  times  the  ordinarily  fatal  dose.  This  acquired  Im- 
munity at  first  sight  resembles  the  tolerance  developed  for  morphine 
and  other  poisons,  but  is  different  in  character.  For  in  the  latter 
case,  the  organism  no  longer  reacts  to  the  poison,  which  has  become 
one  of  its  usual  constituents,  exactly  as  a  fresh  water  organism  may 
slowly  be  rendered  tolerant  to  sea  water,  the  salts  of  which  are  gradu- 
ally added  to  the  fresh  water  and  come  to  form  i)art  of  the  normal 
environment  of  the  organism.  On  the  other  hand,  when  immunity 
to  a  toxin  is  acquired  by  repeated  administration,  the  organism  forms 
a  new  antagonistic  substance  known  as  anfifo.rin,  A\hich  pre\eirts  the 
toxin  from  ha\ing  any  edcct  by  forming  a  loose  conil)in:ition  with  it, 
wliicli  is  innocnoiis.  Mhrhch  has  attempted  to  explain  the  formation 
of  antitoxin  iti  his  well-known  side-chain  hypothesis  by  supposing  that 
toxins  combine  with  certain  components  of  the  li\ing  cells  and  that 
tlir  organism  reacts  by  forming  thos(^  comjionents  in  excess  and  free- 
ing tlicin  ill  tlir  Mood  scrum.     W'licii  toxin  is  injected  into  an  iinnnme 


TOXINS  AND  ANTITOXINS  495 

aniiiiHl,  it  attaches  itself  to  these  bcxHes  in  the  blood  and,  its  affinity 
being  satisfied,  it  can  no  longer  become  linked  to  the  cells  as  it  would  in 
an  unprotected  animal;  the  poisonous  action  is  thus  prevented  because 
the  toxin  is  unable  to  combine  with  the  cells  on  which  it  ordinarily  acts. 
The  organism  forms  these  antitoxins  far  in  excess  of  what  is  necessary 
to  neutralize  the  quantity  of  toxin  administered.  And  this  excess  can 
be  obtained  by  bleeding  the  immune  animal  and  collecting  the  serum; 
and  when  injected  into  an  untreated  animal  this  antitoxic  serum 
lends  it  a  certain  degree  of  immunity  to  the  subsequent  injection  of 
the  original  toxin.  The  use  of  this  antitoxic  serum  may  thus  pro- 
tect animals  from  the  toxin  of  a  disease,  provided  it  be  administered 
early.  After  the  toxin  has  reached  the  tissues,  antitoxin  is  of  less 
benefit  owing  to  the  damage  already  done,  and  the  later  the  antitoxin 
is  employed  the  less  beneficial  action  it  has.  Each  antitoxic  serum 
antagonizes  only  the  toxin  which  has  been  employed  in  its  production, 
and  affects  only  the  toxin  and  not  the  organism  which  may  have  pro- 
duced it.  For  example,  the  antitoxin  for  diphtheria  toxin  has  no 
influence  on  tetanus  toxin  and  is  powerless  against  the  diphtheria 
bacillus,  which  grows  readily  in  the  antidiphtheritic  serum.  On  the 
other  hand  diphtheria  toxin  has  no  eflfect  in  an  animal  protected  by 
an  efficient  dose  of  the  diphtheria  antitoxin.  Each  toxin  must  thus 
be  combated  by  the  corresponding  antitoxin,  and  the  infection  is  not 
antagonised,  but  only  the  poison  produced  by  the  organism. 

The  immunity  acquired  by  treating  an  animal  with  a  toxin  (active 
immunity)  persists  in  greater  or  less  degree  for  many  months  or  years, 
but  the  passive  immunity  given  by  the  injection  of  antitoxic  serum  is 
lost  comparati^^ely  soon  owing  to  the  destruction  and  excretion  in  the 
urine  of  the  antitoxin. 

The  antitoxic  sera  are  entirely  devoid  of  action  except  as  antidotes 
to  the  toxin,  provided  they  are  injected  into  animals  of  the  same 
species  as  that  from  which  they  are  obtained.  In  therapeutics,  animal 
serum  has  to  be  employed  in  man,  and  occasionally  this  gives  rise  to  the 
symptoms  which  are  liable  to  arise  when  ordinary  serum  is  injected 
into  an  animal  of  another  species.  These  symptoms  are  chiefly  skin 
eruptions,  such  as  erythema  and  urticaria,  fever  and  rheumatic  pains 
in  the  joints  and  muscles,  and,  though  unpleasant  and  sometimes 
alarming,  have  no  serious  results.  They  are  not  due  to  the  antitoxin 
as  such  but  to  other  constituents  of  the  foreign  serum,  and  are  equally 
liable  to  arise  when  animal  serum  devoid  of  any  antitoxic  action  is 
injected  into  man. 

A  new  danger  is  beginning  to  be  recognized  in  the  use  of  these  foreign 
sera  from  their  leading  to  the  state  of  Anaphylaxis.  When  a  foreign 
protein  is  injected  hypodermically  or  intravenously,  the  animal  after 
about  15  days  shows  an  extraordinary  sensiti\'eness  to  any  subsequent 
injection  of  the  same  protein.  Very  small  quantities  suffice  to  cause 
alarming  or  even  fatal  collapse  in  man  and  some  animals,  while  in 
others  {e.  g.,  the  guinea-pig)  the  second  injection  proves  fatal  by  im- 
mediate constriction  of  the  bronchioles,  which  leads  to  asphyxia.    This 


4<)()  SIJBSTAXCES  ACTISC  AFTER  ABSORPTION 

sensitivnicss  is  very  specific  for  cacli  i)r()tciii  and  lasts  in  man  for  many 
years  ])erliai)s  thronjihont  life:  thus  a  person  who  has  once  received 
antitoxic  horse  serum  may  be  fatally  poisoned  by  a  second  treatment 
with  horse  serum,  even  after  many  years,  but  ^^'ill  show^  no  reaction  to 
treatment  witli  the  serum  of  other  animals.  It  is,  therefore,  of  great 
importance  in  the  use  of  these  sera  to  ascertain  if  horse  serum  has  been 
previously  used  for  diphtheria  or  any  other  purpose.  Anaphylaxis  is 
only  de\'eloped  after  10-14  days,  so  that  repeated  injections  may  be 
made  without  danger  for  a  week  or  more. 

Apart  from  their  action  on  the  toxins,  serums  may  also  be  specifi- 
cally bactericidal,  destroying  or  retarding  the  growth  of  the  bacillus 
while  affecting  the  toxin  to  a  less  extent.  But  these  may  be  better 
treated  of  in  connection  with  the  microbes  on  which  they  act  and  by 
which  they  are  formed. 

Antidiphtheritic  Serum. 

When  a  horse  is  treated  A\ith  injections  of  gradually  increasing 
doses  of  diphtheria  toxin,  it  acquires  immunity  to  this  poison,  and  its 
serum  is  found  to  neutralize  the  effects  of  large  amounts  of  toxin 
injected  into  other  animals.  Blood  is  then  drawn  from  the  immunized 
horse,  the  serum  is  allowed  to  separate  and  is  collected  in  sealed  tubes; 
some  antiseptic  such  as  carbolic  acid  or  cresol  is  added  to  preserve  it. 
The  amount  of  antitoxin  in  any  serum  must  be  ascertained,  and  this 
is  done  by  animal  experiment,  the  antitoxin  unit  being  the  amount 
necessary  to  protect  an  animal  against  100  times  the  fatal  dose  of 
toxin  for  a  guinea-pig  of  250  G.  weight.  The  antidiphtheritic  serum 
is  thus  sent  out  standardized  in  units,  some  preparations  containing 
100  units  in  the  c.c.  and  others  as  many  as  300  or  even  500  units. 

Serum  ANTmiPHXHERicuM  (U.  S.  P.),  Antidiphtheritic  Serum,  or  Dfph- 
thcria  Antitoxin,  the  serum  of  a  horse  immvmized  by  the  injection  of  diphtheria 
toxin,  kept  in  sealed  glass  tubes  in  the  dark  and  at  a  low  temperature.  It 
is  a  yellowish  fluid,  often  slightly  turbid,  and  with  a  slight  odor  of  an  anti- 
septic. Each  tube  bears  a  label  giving  the  number  of  antitoxin  units  con- 
tained, tlie  date  at  which  the  serum  was  tested,  and  the  date  beyond  which 
it  will  have  deteriorated  aiipreciably.  Average  dose,  3000  units;  i^rophylactu' 
dose,  500  units.  This  dose  may  be  reiieated  after  24  hours  if  necessary.  Anti- 
toxic serum  slowly  loses  its  power  and  should  not  Ijc  used  if  more  than  a  year  old. 

The  antitoxin  of  the  serum  is  i)recii)itatetl  along  with  the  globulins  when 
sucli  neutral  salts  as  ammonium  sulphate  are  added,  and  the  precipitate  may 
1)(!  redissolved  by  dialysing  off  the  excess  of  salt.  In  this  way  a  more  con- 
centrated solution  may  be  obtained,  and  many  such  preparations  are  on  the 
market  under  sucli  designations  as  "  concentrated,"  "purified,"  or  "refined"  dii)h- 
Iheria  antitoxin.  They  have  the  advantage  that  less  fluid  has  to  be  injected 
tliaii  if  the  serum  is  used.  The  serum  may  also  be  dried  at  low  tempefatures 
and  redissolved  for  use;  in  this  form  it  preserves  its  activity  better  than  in  the 
li(iuid  form. 

The  use  of  this  scrum  has  revolutionized  the  treatment  of  diph- 
theria, and  has  reduced  the  mortality  in  this  disease  to  about  one- 
tliinl  or  less  of  that  ])r('\  ailing  before  Bchring  introduced  the  method 


TOXINS  AND  ANTITOXINS  497 

ill  ISO.').  The  syini)toms  improve  within  24  hours,  the  course  of  the 
(Usease  is  cut  short,  and  there  is  not  the  fatal  tendency  to  spread  to  new 
surfaces  which  was  formerly  seen.  It  is  not  yet  determined  how  far 
he  diphtheria  paralysis  is  prevented  by  the  serum.  The  serum  has  not 
direct  action  on  the  bacilli  of  diphtheria,  but  it  antagonizes  the  toxin 
formed  by  them  and  thus  prevents  the  death  of  the  cells  on  which 
the  bacilli  are  growing;  these  protected  cells  then  overcome  the  invaders 
and  the  local  lesion  therefore  improves  rapidly. 

The  remedy  must  be  applied  immediately,  for  when  the  tissues  have 
been  exposed  to  the  toxin  for  some  time  the  antitoxin  has  much  less 
antidotal  effect.  For  example,  the  prognosis  is  about  four  times  as 
bad  if  antitoxin  is  injected  on  the  third  day  as  if  it  had  been  used  on 
the  second  day  of  the  disease.  It  is  also  effective  as  a  prophylactic 
for  those  exposed  to  the  infection.  The  antitoxin  must  be  injected 
subcutaneously  or  intramuscularly  in  large  quantities,  and  it  is  desirable 
to  have  a  serum  containing  a  large  number  of  units,  because  a  weak 
serum  can  only  be  effectiA-e  if  injected  in  large  doses,  and  these  tend  to 
induce  skin  eruptions  and  other  unpleasant  features.  Only  a  few  c.c. 
of  a  strong  serum  are  necessary,  and  these  do  not  contain  enough  of  the 
foreign  components  to  cause  these  symptoms.  In  severe  cases  the 
serum  may  be  injected  intravenously;  it  has  no  action  when  taken  by 
the  mouth. 

Antitetanus  Serum. 

The  tetanus  bacillus  forms  a  toxin  which  induces  powerful  tetanic 
spasms  from  an  action  on  the  spinal  cord  similar  to  that  of  strychnine. 
These  may  be  elicited  by  the  injection  of  the  toxin  and  also  arise 
from  its  absorption  from  wounds  infected  with  the  bacillus.  An 
antitoxin  is  formed  by  immunizing  horses  in  the  same  way  as  the 
antitoxin  of  diphtheria  poison,  and  this  injected  into  animals  protects 
them  from  tetanus  toxin.  In  tetanus  infection  from  wounds,  howe^-er, 
the  toxin  reaches  the  spinal  cord,  not  through  the  lymph  and  blood- 
vessels, but  by  travelling  along  the  nerve  fibres,  while  the  antitoxin 
circulates  in  the  blood  and  reaches  the  nerve  fibres  and  cells  with 
difficulty  (INIeyer  and  Ransom).  There  is  thus  little  opportunity  for 
the  neutralization  of  the  toxin  except  that  circulating  in  the  blood,  and 
the  results  of  treatment  w'ith  this  serum  are  much;  less  striking  than 
those  of  the  antidiphtheritic  serum.  But  if  the  serum  can  be  injected 
early,  before  the  spinal  cord  has  been  attacked  by  the  toxin,  its  effects 
are  specific,  and  it  is  therefore  used  as  a  prophylactic  in  cases  where 
tetanus  infection  is  probable,  and  with  the  best  results. 

The  antitetanus  serum  is  standardized  in  the  same  way  as  the  anti- 
diphtheria  serum  and  should  not  be  used  when  more  than  a  year  old. 
It  is  injected  in  quantities  containing  20-100  units,  which  may  be 
repeated. 

Antimeningitis  Serum. 

Cerebrospinal  meningitis  is  due  to  an  infection  with  Weichselbaum's 
Diplococcus  intracellularis,  and  a  serum  has  been  prepared  by  treating 
32 


4US  SUBSTANCES  ACTING  AFTER  ABSORPTION 

horses  with  the  toxins  of  these  organisms,  and  hiter,  when  a  partial 
ininiunit\-  has  been  reached,  })y  infecting  them  with  the  living  microbes. 
The  serum  is  then  obtained  in  the  same  way  as  the  antidij)htheritic 
serum.  This  serum  has  been  injected  subcutaneously  in  cerebrospinal 
meningitis,  but  the  best  results  are  obtained  by  its  injection  into  the 
spinal  canal.  Dose,  10-15  c.c.  or  more.  The  mortality  of  this  form  of 
meningitis  has  fallen  very  materially  since  this  treatment  was  instituted 
b\'  Flexner. 

Antivenin. 

The  poisons  secreted  by  the  poisonous  snakes  contain  toxins,  and 
an  antitoxic  serum  prepared  by  Calmette  has  been  termed  anti\enin. 
It  protects  animals  against  a  dose  of  snake  poison  which  would  other- 
wise be  fatal  and  has  also  been  used  with  success  in  snake  bite  in  man. 
But  the  effects  of  snake  bite  manifest  themselves  so  rapidly  that  there 
is  not  the  same  opportunity  of  using  this  serum  as  there  is  in  the  case 
of  diphtheria.  And  the  poison  of  different  species  of  snakes  varies 
in  comj^osition  to  some  extent.  When  the  antivenin  is  available, 
however,  its  injection  should  certainly  form  part  of  the  treatment  of 
snake  bite. 

Many  other  immune  sera  have  been  proposed,  but  as  yet  none  of 
them  ha\'e  been  generally  accepted  as  of  value. 

Toxins  arc  also  found  in  a  mniil)er  of  the  higher  plants. 

Ricin  is  an  intensely  poisonous  albumin  found  in  the  seeds  of  Ricinus  coni- 
niunis  along  with  castor  oil,  which  does  not  itself  contain  this  pi'iiu'ii)lc,  however. 
Ricin  is  poisonous  in  doses  of  about  t,to,7  milligram  per  kilogram  body  weight 
injected  su})cutancously,  but  seldom  causes  any  symptoms  when  swallowed, 
as  it  is  apparently  destroj^ed  for  the  most  part  by  the  digestive  ferments.  It 
is  thus  among  the  most  powerful  of  the  vegetable  poisons  when  it  is  injected 
subcutaneously.  Death  often  occurs  only  several  daj^s  after  the  injection  in 
animals,  and  in  the  interval  no  symptoms  make  their  appearance  except  some 
loss  of  appetite,  and  toward  the  end,  diarrhoea  and  vomiting.  Post-mortem, 
the  bowel  is  found  inflamed  and  congested  and  contains  ecchj-moses;  blood 
is  found  in  the  serous  cavities,  and  extravasations  ma}'  occur  in  various  other 
organs,  although  not  so  uniformly  as  in  the  bowel.  Among  the  most  obvious 
lesions  arc  the  innumeral)le  ecchymoscs  in  the  great  omentum  and  the  swelling 
of  the  abdominal  lymph  glands,  which  generally  contain  numerous  small  lurnior- 
i-hages.  Microscopical  examination  reveals  small  foci  of  necrosed  tissue  in  the 
liver,  spleen,  intestiile,  stomach,  and  other  organs.  Ricin  seems  to  l)e  excreted 
by  th(!  intestinal  epithelium,  which  may  explain  the  violence  of  its  action  here, 
aithoujfh  it  acts  as  a  poison  in  many  other  ti-ssues.  It  is  a  powerful  irritant, 
inducing  inflanuiiaiion  and  siii)puration  when  it  is  injected  subcutaneously,  or 
is  applied  to  the  conjunctiva.  On  tlic  other  hand  it  has  little  or  no  irritant 
action  on  the  mouth  and  throat,  and  is  digested  and  rendered  harmless  in  the 
stomach.  Tlu;  mucous  membrane  of  the  nose  is  irritated  by  the  inhalation  of  the 
powder  in  many  persons.  This  toxalbumin  has  a  very  characteristic  action  on 
the  blood.  When  a  drop  of  a  dilute  solution  is  added  to  a  test-tube  of  detibri- 
iiated  blood,  the  corpuscles  soon  fall  to  the  bottom,  leaving  the  clear  serum 
above,  an(l  the  blood  does  not  filter  through  i)aper  any  longer,  the  corpuscles 
all  remaining  ()n  the  tilter,  the  serum  jiassing  through  colorless.  This  is  due 
to  the  aggluthuition  of  the  red  cells,  which  are  formed  into  masses  and  thus 
fail  to  pass  through  the  jjores  of  the  filter.  Filirin  does  not  seem  to  be  formed 
in  the  i)i-()ce.ss,  as  was  at  one  time  supjxjsed,  but   the  nature  of  the  cementing 


BENZOIC  ACID  •  499 

substance  is  unknown.  Stilhnark  sup])()sc(l  that  ricin  I'ornuMl  these  masses  of 
red  cells  in  the  bloodvessels,  and  that  the  symptoms  were  due  to  the  emboli 
resulting,  but  this  is  certainly  incorrect,  for  the  blood  of  immune  animals 
reacts  in  the  same  way,  yet  these  are  not  poisoned  b}^  many  times  the  usual 
fatal  dose  of  ricin. 

Ehrlich  found  that  animals  rapidlj'  acquire  immunity  to  the  action  of 
ricin,  if  thc}^  receive  for  some  time  small  non-toxic  doses.  From  this  dis- 
covery has  arisen  the  Ehrlich  side-chain  theory,  which  plays  such  an  important 
role  in  medicine  at  the  present  time.  By  gradually'  increasing  the  daily  amount 
of  ricin,  rabljits  have  attained  an  inmiunitj"  of  5000,  that  is,  they  are  not 
affected  b.y  5000  times  as  much  ricin  as  would  have  killed  them  had  no  pre- 
liminary treatment  been  instituted. 

Ricin  and  its  antitoxin  are  not  used  in  therapeutics,  but  ricin  has  repeatedly 
given  rise  to  poisoning,  from  the  beans  being  taken  as  a  substitute  for  the  oil. 
Cattle  have  also  been  poisoned  by  being  fed  on  the  refuse  of  castor  oil  beans 
after  the  oil  had  been  expressed. 

Another  vegetable  toxin  which  resembles  ricin  very  closelj^  in  its  effects  is 
Abrin,  which  is  obtained  from  the  seeds  of  Abrus  precatorius  or  jequirity, 
the  familiar  scarlet  and  black  beans,  which  are  often  formed  into  necklaces. 
Abrin  contains  two  poisons,  a  globulin  and  an  albumose,  of  which  the  former 
is  the  more  powerful.  It  induces  the  same  sj^mptoms  as  ricin,  but  is  less  poison- 
ous, and  imniunitj'  can  be  accjuired  in  the  same  way.  Animals  which  are 
immune  to  ricin  are  not  more  resistant  to  the  action  of  abrin  than  others, 
because  the  two  poisons  form  different  antitoxins.  Al^rin  or  jequirity  has 
been  used  as  an  irritant  to  the  e3'e  in  cases  of  granular  lids  and  of  corneal  opaci- 
ties. It  causes  an  acute  inflammation  which  improves  the  condition  in  some 
cases,  but  it  must  be  regarded  as  an  exceedingly  dangerous  remedy,  as  the 
inflammation  is  entirely  beyond  the  control  of  the  surgeon.  In  animals  the 
eye  is  often  completely  destroj^ed  by  the  application  of  abrin,  w'hile  in  other 
experiments  enough  of  the  drug  is  absorbed  to  cause  fatal  poisoning. 

Crotin  is  another  toxin,  which  is  found  in  the  Croton  Tiglium,  but  which 
does  not  pass  into  croton  oil.  It  is  less  poisonous  than  ricin  and  abrin,  but 
resembles  them  in  most  other  points,  except  that  it  does  not  cause  agglutina- 
tion of  the  blood  cells  of  certain  animals,  while  ricin  and  abrin  have  this  effect 
in  all  kinds  of  blood  hitherto  examined. 


XXXIV.     BENZOIC  ACID. 

Benzoic  acid  possesses  almost  the  same  action  as  salicylic  acid  in 
the  body,  and,  like  it,  is  poisonous  only  in  comparatively  large  quan- 
tities. It  seems  to  be  equally,  or  according  to  some  observers,  more 
strongly  antiseptic,  and  like  salicylic  acid  irritates  the  mucous  mem- 
branes, while  its  salts  are  practically  devoid  of  this  last  property. 
Benzoic  acid  is,  however,  apparently  less  stimulant  to  the  central 
nervous  system,  and  the  characteristic  affections  of  the  hearing  and 
sight  have  not  been  observed  under  it. 

In  man  very  large  quantities  of  benzoic  acid  and  sodium  benzoate 
sometimes  produce  nausea  and  uomiting,  the  vomited  matter  rarely 
being  tinged  with  blood.  A  certain  sedative  action  on  the  central 
nervous  system  is  also  said  to  be  observed,  and  an  increased  expectora- 
tion of  mucus  is  produced  in  cases  of  bronchial  irritation.  The  pulse 
is  somewhat  accelerated. 

In  the  dog  tremors  and  convulsions  ha^'e  been  obser\'ed,  and  ataxia, 
paresis  and  eventually  complete  paralysis  of  the  limbs  and  trunk  follow, 


:)0()  SUBSTANCES  ACTING  AFTER  ABSORPTION 

the  trinpcraturo  falls,  and  death  occurs  from  asi)hyxia.  The  heart  and 
respiration  are  first  accelerated  and  then  slowed,  from  a  direct  action 
on  the  heart  and  on  the  respiratory  centre.  Vomiting  occurs  when  the 
acid  or  the  salts  are  given  by  the  mouth.  Post-mortem  the  gastric 
mucous  membrane  has  been  found  to  be  eroded  and  ecchymosed,  even 
when  the  salts  or  acid  have  been  injected  subcutaneously  or  intra- 
venously, so  that  the  benzoates  and  benzoic  acid  would  seem  to  have  a 
specific  action  on  the  gastric  mucous  membrane  quite  apart  from  their 
irritant  effects  when  applied  locally. 

In  frogs  fibrillary  contractions  and  convulsions  are  obser\'ed,  fol- 
lowed by  weakness  and  paralysis  of  the  spinal  cord.  Ihemorrhages 
have  also  been  found  in  the  stomach  when  the  drug  was  injected  into 
a  lymph-sac. 

Benzoic  acid  (CeHsCOOH)  combines  with  glycocoll  in  the  l)ody  to 
form  hippuric  acid  (CeHaCO — NHCH2C00ri),  which  is  excreted  in  the 
urine;  in  the  dog  this  synthesis  appears  to  occur  only  in  the  kidney, 
while  in  other  animals  some  other  organs  are  also  capable  of  carrying 
it  out.  Some  of  the  benzoic  acid  escapes  in  the  urine  unchanged,  how- 
ever, the  proportion  of  hippuric  acid  formed  apparently  varying  with 
the  general  health  and  the  condition  of  the  kidneys,  and  also  with  the 
dose  administered;  and  some  appears  to  be  excreted  in  combination 
with  glycuronic  acid  when  very  large  doses  are  administered.  The 
amount  which  is  formed  to  hippuric  acid  does  not  increase  significantly 
when  glycine  is  administered  along  with  benzoic  acid,  yet  the  glycine 
seems  to  lessen  the  tendency  to  con^'ulsions  in  animals.  Traces  of 
benzoic  acid  are  found  in  the  saHva  of  the  dog  after  its  administration, 
but  it  does  not  seem  to  be  excreted  here  in  man.  In  birds  benzoic 
acid  is  excreted  by  the  kidneys  as  ornithuric  acid  (Ci3HooX204),  from 
which  benzoic  acid  can  be  split  off,  leaving  ornithin.  Benzoic  acid 
often  increases  the  nitrogen  eliminated  in  the  urine,  so  that  in  these 
cases  it  augments  the  decomposition  of  the  proteins  like  salicylic  acid; 
in  other  in^•estigations  no  material  change  has  been  observed,  probably 
because  the  benzoic  acid  was  changed  too  ra]>idly  to  hippuric  acid  to 
admit  of  its  action  on  the  metabolism  being  de\eloped.  It  difi'ers  from 
salicylic  acid  in  reducing  the  uric  acid  excretion.  Some  diuresis  occurs 
after  benzoic  acid. 

Cinnamic  acid  (Cells — CH  =  CH — COOII)  seems  to  resemble  benzoic 
acid  in  its  i)harmacological  characters,  but  has  not  been  so  carefully 
examined.  It  increases  the  leucocytes  of  the  blood  and  the  uric  acid 
of  the  urine  to  a  marked  degree. 

'  Preparations. 

AciDLM  Bknzoicum  (U.  S.  p.,  B.  p.)  (CoHsCOOH),  benzoic  acid  or  flowers 
of  Ijenzoiii,  is  jM-cpared  from  benzoin  by  sublimation,  or  from  toluol,  and  con- 
sists of  white,  feathery  crystals,  almost  odorless,  with  a  warm  acid  taste,  very 
iiis()lul)l((  in  water,  soluble  in  alcohol,  etlier,  fixed  and  volatile  oils  and  in  alkaline 
sohitioiis.    0.5  (1.  {7\  Ki's);  H-  1*-.  5-15  ^rs.,  in  powder  or  i)ill. 

Truclmcus  Acidi  Bcnzoici  (U.  P.),  eacli  conlaiiis  '.  i!;r. 


BENZOIC  ACID  501 

Sodii  Benzoas  (U.  S.  P.,  B.  P.),  easily  soluble  in  water.  1.0  G.  (15  grs.); 
B.  P.,  5-80  grs.,  in  solution. 

Amiiinnii^Brnzoas  (U.  8.  P.,  B.  P.),  1.0  G.  (15  grs.);  B.  P.,  5-15  grs. 

The  Balsams  arc  mixtures  of  resin,  volatile  oils,  benzoic  and  cinnamic  acids 
and  their  esters  and  small  quantities  of  other  aromatic  bodies. 

Benzoinum  (U.  S.  P.,  B.  P.),  benzoin,  a  balsam  obtained  from  Styrax  Ben- 
zoin and  other  species,  varies  in  its  composition  with  its  place  of  origin,  but 
contains  much  less  cinnamic  acid  than  the  other  balsams.    1  G.  (15  grs.).        _    . 

Styrax  (U.  S.  P.),  or  storax,  a  balsam  froni  Liquidambar  orientalis,  contains 
resins,  cinnamic  acid  and  its  esters.    1  G.  (15  grs.). 

Tinclura  Benzoini  (U.  S.  P.),  1  c.c.  (15  mins.). 

TiNCTURA  Benzoini  Composita  (U.  S.  P.,  B.  P.)  contains,  in  addition  to 
benzoin,  storax,  aloes  and  balsam  of  Tolu,  and  was  formerly  known  as  Bal- 
samum  Traumaticum.  A  number  of  old  remedies  resembled  it  in  composition, 
such  as  Friar's  balsam,  Turlington's  balsam,  Jesuits'  drops,  etc.  2  c.c.  (30 
mins);  B.  P.  30-60  mins. 

Balsamum  Peruvianum  (U.  S.  P.,  B.  P.),  Balsam  of  Peru,  a  balsam  obtained 
from  Toluifera  Pereirai  (U.  S.  P.),  or  Myroxylon  Pereirse  (B.  P.),  contains  cin- 
namic and  benzoic  acids  (traces)  and  theii-  esters,  and  resins.  Apphed  externally, 
either  alone  or  in  alcoholic  solution.    1  c.c.  (15  mins.). 

Bahaimnn  Tolutamim  (U.  S.  P.,  B.  P.),  Balsam  of  Tolu,  a  balsam  obtained 
from  Toluifera  Balsamum  or  Myroxylon  Toluiferum,  resembles  balsam  of  Peru 
in  composition,  but  contains  more  benzoic  acid.    1  G.  (15  grs.). 

Syrupus  Tolutanus  (U.  S.  P.,  B.  P.),  16  c.c.  (4  fl.  drs.);  B.  P.,  30-60  mins. 

Tinclura  Tolutana  (U.  S.  P.,  B.  P.),  2  c.c.  (30  mins.);  B.  P.,  30-60  mins.. 

Therapeutic  Uses. — Benzoic  acid  and  its  sodium  salt  have  been  sug- 
gested as  antiseptics  and  seem  to  be  quite  as  satisfactory  as  salicylic 
acid,  but  have  never  been  widely  employed.  Benzoin  and  the  balsam 
of  Peru  are  used  extensively  in  parasitic  skin  diseases,  especially  in 
scabies.  Internally  the  benzoates  have  been  employed  as  substitutes 
for  salicylic  acid  in  acute  rheumatism,  but  have  not  proved  efficient. 
Sodium  benzoate  has  been  administered  as  an  intestinal  disinfectant 
and  as  an  antiseptic  and  slight  irritant  in  diseases  of  the  genito- 
urinary tract,  such  as  cystitis  and  gonorrhoea.  It  was  formerly  sup- 
posed that  benzoic  acid  lessened  the  uric  acid  excretion  and  dissolved 
the  uric  acid  deposits  in  the  bladder  and  tissues  by  forming  hippuric 
acid,  but  this  is  now  recognized  to  be  erroneous,  and  the  treatment  of 
gout  and  other  diseases  based  on  this  theory  may  be  considered  obsolete. 
Ammonium  benzoate  has  been  given  to  increase  the  acidity  of  the 
urine,  but  is  not  so  efficacious  as  the  acid  sodium  phosphate. 

Benzoic  acid  is  still  used  as  an  ingredient  in  expectorant  mixtures, 
in  which,  however,  it  is  generally  prescribed  as  the  simple  or  com- 
pound tincture  of  benzoin,  or  as  one  of  the  Tolu  preparations.  It  is 
said  to  be  beneficial  in  cases  in  which  the  mucus  is  tenacious  and  is 
coughed  up  Avith  difficulty.  The  syrup  of  Tolu  may  be  regarded 
simply  as  a  flavoring  ingredient,  for  it  contains  too  little  of  the  balsam 
to  have  any  other  effect. 

Balsam  of  Peru  and  pure  cinnamic  acid  have  been  administered  by  hypo- 
dermic and  intravenous  injection  and  by  the  mouth  in  pulmonary  tuberculosis, 
in  the  belief  that  they  would  induce  irritation,  inflammation  and  subsequent 
cicatrization  of  the  tubercular  nodules,  but  there  is  no  reason  to  suppose  that 
they  have  any  such  effect,  and  the  treatment  has  never  advanced  beyond  the 
experimental  stage. 


502  SUBSTANCES  ACTING  AFTER  ABSORPTION 

When  tlic  l)alsaiiis  are  administered  in  large  quantities,  the  addition  of  an 
at'id  to  tlie  urine  is  followed  by  the  formation  of  an  abundant  ])recipitate  in 
some  cases,  and  this  has  given  rise  to  the  belief  that  they  tend  to  irritate  the 
kidneys.  The  precipitate  appears  to  be  not  albumin  but  the  resin  in  most 
cases,  however,  for  it  is  dissolved  bj'  the  addition  of  alcohol. 

Bibliography. 

C.  Virchow.     Ztschr.  f.  phj's.  Chem.,  vi,  p.  78. 

Stockman.     Brit.  Med.  Journ.,  1890,  i,  p.  13G.5. 

Kumagawa.     Virchow's  Arch.,  cxiii,  p.  1.34. 

Braulioam  u.  Nowack.     Coiitralbl.  f.  klin.  Mod.,  1889,  p.  409. 

Richter  u.  Spiro.     Arch.  f.  cxp.  Path.  u.  Pharm.,  xxxiv,  p.  289. 

Wiener.     Ibid.,  xl,  p.  313. 

Rost,  Franz,  and  Weitzel.     Arb.  a.  d.  Kaisorl.  Grsundhoitsamtp.,  xlv,  p.  42.'). 

Pribram.     Ibid.,  li,  p.  372. 

Lewandowsky.     Ztschr.  f.  khn.  Med.,  xl,  p.  202. 

Ulrici.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlvi,  p.  321. 


XXXV.     SOME  MINOR  POISONS. 

1.    Nitrobenzol  Compounds. 

The  nitrobenzol  bodies  are  chiefl^y  of  interest  because  thej'  have  often  given 
rise  to  poisoning  of  late  years  from  their  extensive  use  in  chemical  manu- 
factures and  to  flavor  alcoholic  liquors.  They  are  readily  absorbed  from  the 
skin  and  serious  symptoms  have  followed  the  w^earing  of  clothing  dyed  with 
them.  In  man  nitrobenzol  causes  a  grayish-blue,  cyanotic  color  of  the  skin 
and  visible  mucous  membranes,  often  with  nausea,  vomiting,  great  muscular 
weakness,  marked  dyspna?a,  delirium,  and  some  convulsive  movements  of  the 
face  and  jaws,  less  frequeutl.y  of  the  whole  bod}'.  Total  unconsciousness  and 
coma  are  followed  by  arrest  of  the  respiration. 

These  effects  are  due  in  part  to  changes  in  the  blood,  in  part  to  central 
nervous  action,  in  which  stimulation  and  paralysis  seem  to  follow  one  another. 
The  blood  is  found  of  a  chocolate-brown  color,  and  some  of  the  red  cells  are 
either  deformed  or  entirely  destroj'ed.  l']xamined  with  the  spectroscope,  methff- 
moglol^iii  is  very  often  found  in  it,  while  in  other  cases  an  absorption  line  is 
observed  between  the  yellow  and  the  red,  which  docs  not  seem  to  correspond 
to  that  of  anj^  of  the  ordinary  haMuoglobin  products,  and  has  therefore  been 
called  the  nitrobenzol-hannoglobin  line.  The  blood  contains  a  nmch  smaller 
amount  of  oxygen  than  normall}',  in  some  cases  only  1  per  cent,  instead  of 
17,  and  artificial  respiration  or  even  shaking  the  blood  in  air  fails  to  oxidize  it 
further,  as  the  combination  of  nitrobenzol  and  lurmoglobin  seems  to  be  incapable 
of  absorbing  oxj'gen.  Similar  changes  may  be  iirotluced  in  venous  blood  out- 
side the  b()(h'  by  shaking  it  wath  nitrobenzol.  These  changes  in  the  blood  are 
the  cau.se  of  the  cyanosis,  and  the  imperfect  oxidation  of  the  tissues  leads  to  the 
appearance  of  a  number  of  abnormal  products  in  the  urine,  such  as  luvmato- 
por])hyrin.  In  animals  a  gastro-intestinal  catarrh  is  almost  constantly  produced 
unless  the  intoxication  is  verj^  acute,  and  this  occurs  even  when  the  poison  is 
inhaled  or  injected  sulx'utaneously. 

Metadinitrobenzol  ((\;lI.i(X0,.)2)  has  repeatedly  given  rise  to  poisoning  in 
the  manufacture  of  the  modern  explosives,  such  as  roburite  and  securite.  In 
action  it  resembles  nitrobenzol,  but  is  more  jjoisonous,  and  the  gastric  symp- 
toms are  more  marked.  Amblj'opia  and  jaundice-like  coloration  of  the  skin 
often  occur  from  prolonged  exposure  to  this  poison. 

Picric  Acid  (('cn-j()ll(X02)3)  is  an  irritant  to  the  skin  and  mucous  mem- 
branes, and  in  large  doses  causes  vomiting  and  often  anuria  and  strangury. 
.V  characteristic;  symptom  is  the  yellow,  icteric  coloi-  of  the  skin  and  nmcous 
membranes,  which  is  due,  not  to  true  jaundicr,  luil  to  the  staining  of  the  epi- 


FiOME  MINOR  POISONS  503 

thelium  by  the  acid.  It  produces  lliis  coloration  when  taken  internally,  and 
itching  is  often  conii)laincd  of,  and  some  eczema  or  erythema  has  been  ob- 
served. \'iolent  convulsion  occurs  sometimes,  in  other  cases  collapse.  The 
urine  is  yellow  or  red,  and  contains  some  casts  but  little  or  no  albumin,  and  no 
bile,  tlu!  absence  of  the  last  serving  to  diagnose  the  intoxication  from  jaundice. 
Picric  acitl  tends  to  destroy  the  red  cells  of  the  blood  in  animals,  but  no  marked 
diminution  of  these  has  been  observed  in  man.  It  is  excreted  as  picramic  acid 
(C6H20H.NH2(N02)2)  in  the  urine. 

Bibliography. 

Starkou).     Virchow's  Arch.,  Hi,  p.  4G4. 
Hay.     Practitioner,  xxx,  p.  326. 
Fihhnc.     Arch.  f.  exp.  Pcath.  u.  Pharm.,  ix,  p.  329. 
Lewin.     Virchow's  Arch.,  Ixxvi,  p.  443. 
Stone.     Jour.  Amer.  Med.  Assoc,  October  1,  1904. 
Schrocdcr  u.  Strassman.     Viertlj.  f.  ger.  Med.,  1891,  i,  Suppl.,  p.  138. 
Beck.     Charite-annalen,  xvii,  p.  867. 
Munzer  u.  Palma.     Zts.  f.  Heilk.,  xv,  p.  185. 
Huber.     Virchow's  Arch.,  cxxvi,  p.  240. 

2.    Toluylendiamine. 

Toluylendiamine  (C6H3CH3(NH2)2)  has  never  been  used  in  therapeutics, 
but  it  is  of  importance  from  the  light  wliich  it  has  thrown  on  some  forms  of 
jaundice.  Staclelmann  found  that  its  administration  in  dogs  produced  the 
typical  symptoms  of  icterus,  while  in  cats  the  icterus  was  less  marked,  but 
very  large  (luantities  of  hemoglobin  were  excreted  in  the  urine.  The  expla- 
nation of  this  action  is  the  destruction  of  the  red  cells  in  the  blood,  which  leads 
in  the  dog  to  the  formation  of  large  amounts  of  bile  pigments  in  the  liver.  Some 
of  this  pigment  is  reabsorbed  from  the  bile  vessels  and  leads  to  typical  jaundice. 
The  absorption  is  promoted  by  a  curious  increase  in  the  mucus  secretion  of  the 
bile  ducts,  which  renders  the  bile  more  viscous,  and  by  thus  delaying  its  evacua- 
tion into  the  intestine  favors  its  absorption  into  the  blood.  This  increased  mucus 
formation  is  believed  to  be  due  to  the  action  of  the  poison  on  the  secretory  cells 
of  the  larger  bile  ducts.  The  formation  of  bile  pigment  from  haemoglobin 
liberates  large  ciuantities  of  iron,  which  seems  to  be  stored  in  the  liver,  spleen, 
and  bone  marrow.  In  the  cat  the  hemoglobin  is  not  so  largely  formed  into 
bile  pigment,  but  escapes  in  the  urine.  In  both  animals  some  methsemoglobin 
is  probably  formed.^  According  to  Joannovics  and  Pick  the  hemolysis  is  not 
directly  due  to  the  toluylendiamine,  but  is  the  result  of  bodies  formed  in  the 
liver  under  the  action  of  the  poison. 

Bibliography, 

Stadelmann.     Arch.  f.  exp.  Path.  u.  Pharm.,  xiv,  pp.  231  and  422;  xxiii,  p.  427. 
Engel  u.  Kiener.     Comptes  rend,  de  I'Acad.,  cv,  p.  465. 
Mohrberg.     Arb.  a.  d.  pharm.  Inst,  zu  Dorpat,  viii,  p.  20. 
Joannovics  and  Pick.     Ztschr.  f.  ex.  Path.  u.  Therap.,  vii,  p.  185. 
Cushny.     Journ.  of  Pharmacology,  ii,  p.  531  (Senecio). 

3.   Benzol. 

Benzol,  or  benzene,  is  much  less  poisonous  than  its  hydroxyl  compounds, 
but  may  give  rise  to  symptoms  resembling  those  of  phenol  when  it  is  inhaled 
in  large  quantities.  It  was  at  one  time  suggested  as  a  general  anaesthetic, 
but  the  preliminary  excitement  is  yery  much  greater  than  that  seen  in  the 

1  A  somewhat  similar  action  follows  the  administration  of  Cephalanthin,  the  active 
principle  of  Cephalanthus  occidentalis.  Button-bush  or  Swamp  dogwood  (Mohrberg),  and 
of  the  alkaloids  of  several  species  of  Senecio  such  as  ragwort  and  groundsel. 


504  SUIiSTANCES  ACT  INC.   AFTER  ABSORI'TION 

use  of  c'liloioforni  or  ctlier,  and  i)artakc.s  much  more  of  a  convulsive  character. 
i;vcn  after  unconsciousness  and  aiurstlicsia  is  attained,  the  characteristic 
muscular  tremor  of  the  aromatic  compounds  continues.  In  some  animals  it 
produces  violent  and  prolonged  convulsions,  with  only  partial  loss  of  sensa- 
tion, and  even  large  cjuantities  do  not  cause  the  complete  relaxation  of  the 
muscles  requisite  for  surgical  operation.  It  seems  to  have  little  or  no  irri- 
tant action  on  the  alimentary  canal  or  kidneys  in  animals,  and  is  excreted 
in  i)art  by  the  kidneys  as  phenol  double  sulphate,  in  part  unchanged  by  the 
lungs. 

Santesson  states  that  lurmorrhages  occur  very  frcHjuently  in  fatal  poisoning 
in  man,  and  found  the  same  result  in  experiments  on  rabbits;  he  ascribes  it 
to  fatty  degeneration  of  the  arterial  walls,  which  was  well-marked  in  most 
of  his  "experiments.  A  number  of  cases  of  fatal  intoxication  are  on  record, 
some  of  them  arising  from  the  drug  being  swallowed  l)y  suicides,  ))ut  most  of 
them  from  the  accidental  inhalation  of  large  quantities  in  india-rubber  factories. 
Animals  exposed  to  benzol  vapor  do  not  seem  to  absorb  enough  to  be  seriously 
l)oisoned,  but  when  it  is  injected  subcutaneously  or  applied  over  a  large  skin 
area,  it  proves  fatal  to  them.  It  has  recently  been  noted  that  in  benzol  poisoning 
a  marked  fall  in  the  number  of  the  leucocytes  of  the  blood  occurs  and  this  has 
suggested  the  use  of  benzol  in  some  forms  of  leucsemia;  a  great  diminution  in  the 
white  cells  follows  and  the  general  symptoms  show  a  corresponding  imi)roye- 
ment.  It  is  too  soon  to  state  how  far  the  treatment  leads  to  p(M-nuinent  relief, 
or  how  long  it  may  be  continued. 

Bibliography. 

Santesson.     Arch.  f.  Hygiene,  xxxi,  p.  336;  Skaiul.  Arch.  f.  Physiol.,  x,  p.  1. 
Chassevant.     Arch,  de  Pharmacodynam.,  ii,  p.  235. 

4.  Phloridzin. 

Phloridzin  is  not  used  in  therapeutics,  l)ut  has  attracted  some  attention 
from  its  effects  in  animals,  and  may  therefore  be  mentioned  shortly.  It  is 
a  gIucosid(>  (C21H24O10  +  2H2O)  found  in  the  rootbark  of  the  apple,  i)ear,  cherry 
and  plum  tree.  When  given  in  large  quantities  by  the  mouth  it  sometimes 
causes  some  diarrha>a  in  animals,  but  apart  from  this  its  only  effect  is  glycosuria, 
which  also  follows  its  injection  subcutaneously  or  intravenously.  The  urine 
is  found  to  contain  5-15  per  cent,  or  even  more  of  sugar,  sometimes  along  with 
acetone  and  oxybutyric;  a(!id,  so  that  the  intoxication  seems  at  first  sight  to 
resemble  diabetes  mellitus  in  man  very  closely.  Phloritlzin  induces  the  same 
results  in  man,  and  the  glycosuria  is  not  accompanied  by  any  other  symptom 
generally.  It  differs  from  true  diabetes,  however,  in  the  fact  that  the  sugar 
of  th(>  tjiood  is  not  increased  in  amount.  The  glycosuria  is  not  due  to  any  change 
in  the  general  metabolism  of  the  body,  therefore,  but  to  some  alteration  of  the 
I'cnal  epithelium,  by  which  the  blood  sugar  escapes  into  the  urine,  instead  of 
being  I'etained  in  the  body  and  used  as  a  source  of  energy.  This  has  been 
delinitely  i)roved  by  Zuntz,  who  showed  that  when  phloridzin  was  injected  into 
one  renal  artery,  the  urine  secreted  by  the  corresponding  kidney  containeil 
sugar,  while  that  from  the  other  remained  normal  foi"  some  time.  As  the  avail- 
aljle  sugar  is  drained  off  in  the  urine,  the  tissues  rapidly  manufacture  more  and 
pour  it  into  the  blood.  As  long  as  sufficient  food  is  given,  the  loss  of  sugar  does 
not  seem  to  entail  any  increase  in  the  destruction  of  the  i)roteid  tissues,  l)Ut  wIumi 
])hloridzin  is  given  to  starving  dogs,  the  waste  of  sugar  has  to  be  nuule  uj)  from 
the  tissues,  and  the  nitrogen  of  the  urine  accordingly  rises  in  amount,  while  at 
the  .same  time  the  liver  cells  l)ecome  infill ratinl  with  fat  globules.  The  statement 
that  the  sugar  of  the  milk  is  increased  l)y  |)hloridzin  has  proved  to  be  incorrect. 

(Jlycosuria  may  be  maintainetl  for  an  indefinite  time  if  the  administration  of 
jihldiidzin   be  continued,   and   animals  reco\-er  rapidly   when   the  treatment    is 


SODIUM  CHLORIDE  AND  WATER  50") 

stopped.  The  glucoside  is  probably  excreted  in  the  urine  unchanged,  although 
this  has  not  been  quite  satisfactorily  demonstrated  as  yet.  Phloridzin  may  be 
decomposed  into  a  sugar,  phlorose,  and  phloretin,  which  also  induces  glycosuria. 

Bibliography. 

V.Mering.     Zts.  f.  klin.  Med.,  xiv,  p.  405;   xvi,  p.  431. 
Rosen/eld.     Ibid.,  xxviii,  p.  256. 

Zuntz.     Arch.  f.  Anat.  u.  Phys.  (Phys.  Abth.),  1895,  p.  570. 
Coolen.     Arch,  de  Pharmacodynam,  i,  p.  267;  ii,  p.  255. 

Kulz,  Wright,  Moritz,  Prausnilz,  Cremer,  Ritter,  Lusk.  Zts.  f.  Biol.,  xxvii,  xxviii, 
xxix,  xxxvi. 

Reilly,  Nolan,  and  Lusk.     Amer.  Jour,  of  Phys.,  i,  p.  395. 

Levene.     Jour,  of  Exp.  Med.,  ii,  p.  107. 

Pappenheim.     Arch.  f.  Verdauungskrank,  iii,  p.  421. 

Hildebrandt.     Virchow's  Arch.,  cxxxi,  p.  26. 

Pavy,  Brodie,  and  Siau.     Journ.  of  Phys.,  xxix,  p.  467. 

Loewi.     Arch.  f.  exp.  Path.  u.  Pharm.,  1,  p.  326. 

XXXVI.    SODIUM  CHLORIDE  AND  WATER. 

The  most  typical  example  of  salt-action  is  presented  by  chloride  of 
sodium,  for  this  salt  is  always  present  in  large  quantities  in  the  body, 
and  has  practically  no  specific  action;  the  sodium  and  chloride  ions 
are  ordinary  and  necessary  constituents  of  the  fluids  of  the  body. 
The  action  of  this  salt  is  therefore  limited  to  the  alteration  in  the 
physical  properties .  of  the  fluids,  which  its  presence  in  excess  or  in 
limited  amount  induces.  In  the  same  way  the  action  of  water  is 
due  only  to  its  diluting  the  body  fluids  and  lessening  their  osmotic 
pressure,  and  it  may  therefore  be  described  along  with  that  of  salt. 

Most  of  the  tissues  hitherto  examined  in  regard  to  this  point  have 
proved  permeable  by  both  the  Na  and  CI  ions,  but  in  every  case 
there  is  a  certain  amount  of  resistance  offered  so  that  the  presence  of 
salt  in  the  fluid  round  a  cell  always  prevents  water  from  diffusing  freely 
into  the  interior;  i.  e.,  sodium  chloride  solution  exerts  osmotic  pressure 
on  the  cell.  The  molecular  weight  of  common  salt  being  small,  the 
osmotic  changes  induced  by  it  are  greater  than  those  induced  by  an 
equal  weight  of  most  other  salts,  because  a  larger  number  of  mole- 
cules exist  in  each  gramme.  It  also  dissociates  into  its  two  ions 
more  readily  than  many  others,  and  this  lends  it  still  greater  osmotic 
power. 

A  common  example  of  the  osmotic  action  of  salt  is  seen  in  its  use 
to  preserve  meats  from  putrefaction,  which  it  accomplishes  by  with- 
drawing the  fluids  of  the  meat,  and  thus  rendering  it  dry  and  hard 
and  unsuitable  for  the  growth  of  microbes. 

In  the  same  way  the  Red  Blood  Corpuscles  shrink  in  size  when  they 
are  placed  in  a  solution  of  salt  which  is  stronger  than  the  blood-plasma 
(hypertonic),  because  the  water  is  withdrawn  from  them.  In  dilute 
(hypotonic)  solution,  on  the  other  hand,  or  in  water,  they  swell  up 
because  they  absorb  water,  while  in  solutions  of  the  same  osmotic 
pressure  as  the  plasma  (isotonic)  they  remain  unaltered  in  size. 
When  water  is  absorbed  into  the  corpuscles,  they  swell  up  and  burst, 
and  the  haemoglobin  diffuses  into  the  surrounding  liquid. 


nOfi  SUBSTANCES  ACTING  AFTER  ABSORPTION 

Muscle  is  affected  in  a  similar  way,  strong  salt  solutions  withdraw- 
ing fluid  from  it,  while  weaker  ones  are  absorbed,  and  both  tend  to 
destroy  its  vitality  in  a  longer  or  shorter  time.  In  isotonic  salt  solu- 
tion, on  the  other  hand,  muscle  preserves  its  irritability  for  many 
hours.  Strong  salt  solutions  irritate  exposed  Nerves  from  the  with- 
drawal of  their  fluid  contents,  and  on  the  other  hand,  distilled  water 
first  irritates  and  then  paralyzes  them. 

These  changes  are  undoubtedly  due  to  the  imperfect  permeability  of  the 
cells  b}'  the  sodium  and  chloride  ions,  and  as  regards  the  red  blood  corpuscles, 
it  is  definitely  known  that  salt  penetrates  them  with  the  greatest  difiicuUy, 
if  at  all,  and  the  changes  induced  in  them  by  solutions  of  different  concentration 
and  by  water  are  due  to  tlu^  alteration  of  their  fluid  contents  only.  If  this  were 
ti-ue  for  all  cells,  the  isotonic  solution  would  preserve  them  in  a  normal  con- 
dition until  they  slowly  perished  for  want  of  oxygen  and  from  exhaustion  of 
their  reserve  of  food.  But  this  is  found  not  to  be  the  case,  for  muscle  suspended 
in  isotonic  solution  often  develops  a  more  or  less  rhythmical  series  of  con- 
tractions, while  the  frog's  heart  ceases  to  beat  after  a  time  when  it  is  perfused 
with  isotonic  salt  solution,  although  it  has  not  exhausted  its  energy  entirely. 
Similar  1}'  some  ova  and  fish  living  in  sea  water  die  if  they  are  put  in  a  solution 
of  sodium  chloride  isotonic  with  sea  water,  while  they  live  nuich  longer  in  dis- 
tilled water.  It  is  obvious  that  in  these  instances  no  change  in  the  distribution 
of  the  fluids  can  occur,  for  the  osmotic  pressure  of  the  fluid  is  unchanged.  In 
other  words  the  death  of  these  animals  in  pure  salt  solution  is  due,  not  to  the 
physical  action  of  the  salt  (salt  action),  but  to  the  sodium  ion  exercising  a 
(U^kiterious  effect  on  them.  This  deleterious  action  may  .be  neutralized  by  the 
addition  of  traces  of  salts  of  calcium  or  of  some  other  bivalent  elements,  while  the 
monovalent  kations  have  less  antagonistic  effects  (Loeb).  In  the  natural 
environment  of  living  cells  both  sodium  and  calcium  are  present,  so  that  the 
toxic  effect  of  sodium  (see  Calcium)  can  scarcely  be  observed  except  when  small 
masses  of  tissue  are  thoroughly  washed  with  salt  solution;  as  far  as  the  higher 
animals  are  concerned,  then,  salt  may  be  regarded  as  indifferent  in  itself  and  as 
acting  only  through  changing  the  distribution  of  the  fluids.  And  as  isotonic 
solutions  have  no  osmotic  action,  they  are  entirely  inert. 

Water  or  very  dilute  salt  solutions  penetrate  into  the  superficial 
cells  of  the  Skin,  which  therefore  become  swollen  and  softened.  Con- 
centrated solutions,  on  the  other  hand,  rather  tend  to  draw  fluid  from 
the  surface  cells,  and  this  along  with  the  passage  of  salt  into  them, 
causes  some  mild  irritation.  Neither  salt  nor  w^ater  is  absorbed  into 
the  circulation  through  the  skin  in  mammals.  A  much  greater  ab- 
sorption into  the  superficial  tissues  occurs  on  less  protected  parts, 
such  as  the  cornea,  which  becomes  white  and  clouded  when  strong 
salt  solutions  are  applied  to  it.  Similarly,  either  pure  water  or  strong 
salt  solution  causes  considerable  pain  and  smarting  in  the  nasal  passages, 
or  in  wounds,  from  the  disturbance  of  the  normal  relation  of  salt  and 
fluid  in  the  surface  cells.  Isotonic  solutions,  on  the  other  hand,  cause 
no  pain. 

In  the  Mouth  salt  has  a  characteristic  taste,  and  strong  solutions  act 
as  astringents  here  and  in  the  throat.  In  the  Stomach  its  action  is 
very  nnich  like  that  on  other  mucous  membranes,  hypotonic  solutions 
causing  swelling,  while  hy|)ertonic  solutions  cause  a  withdrawal  of 
fluid  and  a  sliriid<ing  of  the  cells.  This  withdrawal  of  fluid  and  ini- 
bibition  of  salt  may  set  up  such  irritation  as  to  induce  vomiting. 


SODIUM  CHLOh'IDK  AND   WATER  507 

The  digestion  in  the  stomach  (h)e,s  not  always  seem  to  be  im{)roved 
by  salt  in  the  food,  for  even  small  qnantities  have  been  found  to  lessen 
the  acidity  of  the  gastric  juice,  and  the  amount  of  albuminous  food 
absorbed  from  the  alimentary  canal  in  animals  is  but  little  altered 
when  salt  is  added  to  the  food.  It  is  very  possible,  however,  that  a 
small  quantity  of  salt  in  the  food  renders  it  more  palatable  in  many 
instances,  and  thus  increases  the  reflex  fiow  of  the  gastric  juice.  (Com- 
pare Simple  Bitters.)  Dapper  finds  that  the  hydrochloric  acid  of  the 
stomach  is  increased  in  some  persons  and  diminished  in  others  by 
mineral  waters  containing  common  salt  as  their  chief  ingredient.  These 
waters  ha^'e  no  effect  on  the  secretion  directly,  then,  but  may  alter  it 
by  changing  the  nutrition  of  the  gastric  mucous  membrane,  or  by  arous- 
ing secretion  reflexly  by  their  taste. 

Salt  solutions  are  Absorbed  little  in  the  stomach,  largely  in  the 
bowel,  but  considerable  difference  of  opinion  exists  as  to  the  means 
by  which  this  is  accomplished.  An  attempt  has  been  made  to  explain 
aiisorption  by  the  action  of  the  known  physical  processes,  such  as 
diffusion,  osmosis  and  filtration,  but  these  seem  quite  inadequate 
without  the  assumption  that  there  is  a  constant  tendency  for  fluids 
and  for  some  salts  to  pass  inward  from  the  lumen  of  the  bowel. 
This  tendency  ma>'  be  opposed  or  strengthened  by  the  osmotic  pres- 
sure. Thus  hypotonic  solutions  and  water  are  al)sorbed  rapidly, 
because  here  not  only  is  the  natural  flow  inward,  but  the  osmotic 
current  is  in  the  same  direction,  the  fluid  being  of  lower  osmotic 
pressure  than  the  blood  serum.  In  solutions  of  equal  osmotic  pres- 
sure with  the  blood  serum  the  absorption  is  slower,  because  here  the 
natural  ifow  alone  is  active,  while  hypertonic  solutions  are  still  more 
slowly  absorbed  or  may  even  be  increased  at  first,  because  the  osmotic 
pressure  acts  in  the  opposite  direction  from  the  natural  flow.  Ac- 
cordingly, while  hypotonic  and  isotonic  solutions  disappear  rapidly, 
the  absorption  of  the  stronger  solutions  may  be  preceded  by  a  period 
in  which  the  fluid  of  the  bowel  actually  increases,  water  diffusing  into 
it  from  the  blood.  At  the  same  time  the  salt  is  being  absorbed  and 
the  solution  eventually  becomes  isotonic  and  is  absorbed. 

The  Blood  and  Lymph  are  in  turn  affected  by  these  processes.  When 
hypotonic  solutions  pass  into  the  blood  from  the  bowel,  the  proportion 
of  solids  and  liquid  is  of  course  changed  and  fewer  corpuscles  and  less 
solid  matter  are  found  in  the  cubic  millimeter  than  normally  (hydrse- 
mia).  On  the  other  hand,  when  strong  salt  solutions  in  the  bowel 
cause  the  effusion  of  fluid,  the  blood  becomes  more  concentrated  than 
in  ordinary  conditions.  After  the  reabsorption  of  the  fluid,  the  normal 
balance  of  plasma  and  corpuscles  must  be  restored,  and  to  effect  this 
currents  are  set  up  between  the  blood  and  the  fluid  of  the  surrounding 
lymph.  These  currents  h-dve  been  investigated  by  the  injection  of  salt 
solutions  directly  into  the  blood,  and  not  by  their  absorption  from  the 
bowel,  but  the  processes  probably  resemble  each  other  in  their  chief 
features.  When  the  blood  is  rendered  hypertonic  by  the  injection  of 
strong  salt  solution,  the  lymph  at  once  begins  to  pour  into  the  blood- 


nOS  SUBSTANCES  ACTING  AFTER  ABSORPTION 

vessels  by  osmotic  attraction  and  this  leads  to  hydrsemia  and  increased 
capillary  pressure,  the  arterial  tension  remaining  unchanged.  This 
augmentation  of  the  capillary  pressure  in  turn  induces  a  flow  of  lymph 
from  the  bloodvessels  into  the  lymi)h  spaces. 

The  flow  of  lymph  from  the  bloodvessels  is  first,  therefore,  dimin- 
ished in  amount  by  the  presence  of  salt  in  the  intestine  and  blood  and 
then  increased  again  by  the  high  capillary  pressure.  This  interchange 
between  the  blood  and  lymph  is  continued,  because  as  the  salt  is  ex- 
creted by  the  kidneys  and  other  excretory  glands,  a  continual  variation 
ill  the  osmotic  pressure  of  both  blood  and  lymph  occurs. 

The  details  of  the  changes  between  the  blood  and  lymph  under  the 
action  of  salt  and  water  are  still  obscure,  but  there  is  no  question  that 
the  absorption  of  either  of  these  leads  to  an  augmentation  of  the  normal 
exchange  of  these  fluids.  In  particular,  it  is  still  undecided  whether 
the  cells  of  the  vessels  possess  a  secretory  function  similar  to  that  of 
the  secretory  glands,  or  whether  the  whole  process  may  be  attributed 
to  variations  of  osmotic  pressure  and  filtration. 

The  changes  in  the  blood  and  lymph  are  followed  by  an  increased 
activity  of  the  Excretory  Organs.  Thus  the  urine^  is  much  augmented 
by  the  injection  of  salt  solution  into  the  blood,  less  so  by  the  absorp- 
tion of  water  or  salt  solution  from  the  stomach  and  bowel.  A  good 
deal  of  discussion  has  been  carried  on  in  recent  years  as  to  the  cause 
of  the  diuresis  from  salts  and  water,  and  some  authorities  hold  that 
the  presence  of  salt  in  excess  in  the  blood  stimulates  the  renal  cells 
much  in  the  same  way  as  caffeine.  But  a  more  plausible  explanation 
is  that  the  greater  volume  of  the  blood,  following  the  absorption  of 
the  fluid  and  the  increased  flow  of  lymph,  results  in  an  increase  in  the 
capillary  pressure  in  the  glomerulus  and  this  in  turn  promotes  the 
escape  of  fluid  into  the  capsule.  A  more  rapid  flow  through  the  tubules 
follows,  and  the  glomerular  secretion  lies  in  them  for  a  shorter  time, 
so  that  there  is  less  tendency  for  its  constituents  to  be  reabsorbed 
into  the  bloodvessels;  the  fluid  reaching  the  ureters  is  accordingly 
increased,  and  the  dissolved  salts  and  urea  are  also  augmented;  those 
constituents  which  in  ordinary  circumstances  are  absorbed  most  readily 
by  the  epithelium  of  the  tubules  are  increased  more  than  the  others, 
so  that  the  chlorides  and  the  potassium  and  sodium  of  the  urine  rise 
mucli  more  than  the  urea,  ])hosphates  or  sulphates,  even  when  the 
diuresis  is  due  to  the  absorption  of  water.  Cow  has  recently  pointed 
out  that  when  water  or  salt  solution  is  injected  intravenously  or  hypo- 
dermically,  it  has  much  less  diuretic  action  than  when  it  is  absorbed 
from  the  bowel;  no  satisfactory  ex'planation  of  this  observation  has 
been  offered  as  yet. 

Wiien  very  large  amounts  of  isotonic  salt  solution  are  thrown  into 
tlie  blood,  the  organism  may  have  difficulty  in  excreting  it  rapidly 

'  The  following  explanation  of  tho  diuresis  is  based  upon  the  theory  that  all  the  con- 
stituents of  the  urine  are  ex(!relcd  l>y  the  t;lonierulus,  and  thai  some  of  theni,  notal)ly 
much  of  the  lluid  and  the  alkali  chlorides,  arc  reabsorbc^il  in  passing  throuiili  the  lubules. 
See  .lourn    of  I'li.wsiol.,  xxvii,  p.  429;    xxviii,  p.  431. 


SODIUM  CHLORIDE  AND  WATER  509 

enough,  and  the  tissues  are  therefore  found  to  be  swollen  and  (edema- 
tous in  some  parts  of  the  body. 

When  salt  solution  is  injected  into  the  serous  cavities  or  into  the 
lymph  spaces,  absorption  occurs  in  the  same  way  as  from  the  alimen- 
tary canal,  except  that  in  the  case  of  the  serous  cavities  diffusion  seems 
to  play  a  greater,  and  the  other  forces  a  smaller  role,  than  in  the 
stomach  and  intestine. 

The  administration  of  large  quantities  of  fluid,  either  as  water  or 
as  dilute  salt  solution,  might  be  expected  to  have  some  effect  on  the 
general  Tissue  Change,  through  the  increased  movement  of  the  lymph 
flushing  out  the  cells  and  leading  to  a  more  complete  removal  of  the 
waste  products.  As  a  matter  of  fact,  some  increase  in  the  nitrogen 
and  sulphur  eliminated  in  the  urine  has  been  observed  under  the  use 
of  large  quantities  of  w^ater,  but  it  is  impossible  to  estimate  at  present 
how^  far  this  may  be  due  to  the  diuresis  alone;  in  any  case  the  increase 
is  not  by  any  means  so  large  as  is  often  believed,  as  it  only  amounts 
to  some  5  per  cent,  or  less.  Any  salt  solution  causing  an  acceleration 
in  the  movement  of  the  fluids  of  the  body  must  tend  to  facilitate  the 
excretion  of  the  waste  products  in  the  same  way,  but  some  recent 
investigations  indicate  that  in  addition  salt  tends  to  alter  the  protein 
metabolism  through  acting  directly  on  the  cells;  this  action  is  so 
slight,  however,  that  the  resulting  change  in  the  nitrogen  eliminated 
is  concealed  by  the  increase  caused  by  the  more  complete  flushing 
and  diuresis.  The  amount  of  proteins  and  fats  absorbed  from  the 
alimentary  tract  does  not  appear  to  be  altered  by  the  administration 
of  large  amounts  of  water  (Edsall). 

Strong  salt  solutions  injected  into  animals  either  hypoderniically  or  intra- 
venously sometimes  prove  fatal,  apparently  from  the  withdrawal  of  fluid 
from  the  central  nervous  system.  The  sj'mptoms  in  mammals  are  increasing 
lassitude  and  weakness,  with  augmented  reflex  excitability,  tremors,  and  finally 
convulsions.  The  circulation  is  only  slightly  affected  until  just  before  death, 
when  the  blood-pressure  falls  suddenly.  The  red-blood  cells  are  found  to  be 
much  shrunken,  and  haemorrhages  are  found  in  different  organs;  the  lungs 
are  cedematous,  and  the  intestinal  mucous  membrane  is  swollen  and  congested. 

The  Salts  of  the  Urine  are  increased  by  diuresis  from  any  cause,  as 
has  been  stated;  both  sodium  and  potassium  are  augmented,  but  espe- 
cially the  sodium,  which  is  present  in  larger  proportions  in  the  plasma 
and  therefore  forms  a  larger  constituent  of  the  glomerular  secretion. 
This  increase  in  the  sodium  salts  is,  of  course,  particularly  marked 
when  diuresis  is  induced  by  common  salt,  but  when  potassium  salts 
increase  the  urine,  the  sodium  also  generally  predominates  in  it  and 
this  would  eventually  lead  to  the  loss  of  all  the  sodium  in  the  blood 
of  herbivora,  whose  food  contains  large  quantities  of  potassium;  but 
after  a  certain  amount  of  sodium  has  been  lost,  potassium  causes  no 
further  excretion,  so  that  the  tissues  apparently  protect  themselves 
from  the  total  loss  of  sodium  chloride,  which  would  be  fatal  to 
them. 


510  SUBSTANCES   ACTING   AFTER   AHSORPTION 

Bunge  states  that  in  l)()tli  inaii  and  animals  a  diet  rich  in  potassium  causes 
an  ai)pctitp  for  common  salt,  while  a  diet  which  does  not  contain  an  excess 
of  i)otassium  does  not  develop  this  desire.  Thus  herbivorous  animals  and  agri- 
cultural peoples  seek  for  salt,  l)ecause  vegetal)Ie  foods  contain  large  ciuantities 
of  potassium,  while  the  carnivora  and  the  hunting  peoples  require  no  salt  and 
often  have  a  distaste  for  it,  owing  to  their  food  containing  a  larger  relative 
proportion  of  sodium  salts.  This  instinctive  appetite  he  regards  as  a  means 
b}'  which  nature  protects  the  tissues  from  excessive  loss  of  sodium.  Some 
doubt  has  recently  been  thrown  on  this  explanation  of  the  desire  for  salt  by 
Lapicque,  who  discovered  some  African  races  living  on  vegetable  substances 
alone,  and  using  the  ashes  of  the  plants,  which  contain  more  jiotassium  than 
sodium,  as  civilized  peoples  use  ordinary  salt.  He  holds,  therefore,  that  salt 
is  merely  of  value  as  a  flavoring  agent. 

Therapeutic  Uses. — Water  and  salt  are  rarely  or  never  prescribed  as 
such,  but  are  used  to  a  very  large  extent  in  medicine,  and  great  virtues 
have  been  ascribed  to  them  in  a  number  of  pathological  conditions. 

They  are  used  for  their  local  action,  and  for  the  supposed  alterations 
in  the  tissue-change  and  in  the  excretions  produced  by  them  after 
their  absorption  into  the  blood.  In  general,  patients  are  sent  to 
watering  places  and  baths,  and  the  success  of  the  treatment  is  to  a 
considerable  extent  due  to  the  climatic  conditions,  the  change  in  the 
habits  of  life,  the  dietic  treatment  and  the  rest  from  everyday  occu- 
pations. At  the  same  time  the  drinking  of  large  quantities  of  weak 
salt  solutions,  and  the  constant  bathing  in  somewhat  irritating  fluids, 
may  exercise  a  therapeutic  action  in  many  cases,  and  may  at  any  rate 
aid  the  hygienic  conditions.  Whether  the  water  contains  salt  or  not, 
it  must  be  remembered  that  in  bathing  the  action  is  a  purely  k)cal  one, 
for  neither  the  salt  nor  the  water  is  absorbed.  The  slightly  irritant 
effect  on  the  skin  may,  however,  improve  its  circulation  and  nutrition, 
and  thereby  be  efficacious  in  some  skin  diseases.  By  continued  use 
the  sensitiveness  of  the  skin  vessels  to  heat  and  cold  may  also  possibly 
be  deadened.  The  changes  in  the  metabohsm  induced  by  bathing  in 
strong  salt  solution  are  merely  trifling  in  extent,  and  there  is  no  reason 
to  suppose  that  the  bathing  in  itself  has  any  therapeutic  value  what- 
ever. The  efficacy  of  the  treatment  in  bathing  places  is  due  to  the 
dietetic  regimen,  the  cliangc  in  chmate  and  other  factors,  which  are 
popularly  supposed  to  be  merely  accessory  features.  Special  baths 
are  very  frequently  recommended  for  some  diseases,  but  it  must 
be  remembered  that  the  action  is  due  to  the  salt;  the  greater  the 
concentration,  the  greater  is  the  effect  on  the  skin,  and  it  is  of  no 
importance  which  of  the  neutral  salts  is  in  the  solution,  or  whether 
small  traces  of  iron  or  other  metals  are  present;  alkaline  baths  act 
more  on  the  skin  than  others. 

In  diseases  of  the  stomach  the  drinking  of  large  ((uantities  of  water 
or  of  weak  salt  solutions  ma\'  also  be  beneficial.  The  action  is  similar 
to  that  on  the  skin — a  mild  irritation,  owing  to  the  swelling  of  the 
more  su])erfi(i;d  ceils  of  the  epithelium  and  the  increased  movement 
of  the  fluiil  in  llicin  and  in  the  deeper  layers.  In  some  cases  of 
insonniia  hot  water  sonictinies  causes  sleep,  i)rol)al»ly  by  causing  dila- 


SODIUM  CHLORIDE  AND  WATER  511 

tation  of  the  gastric  vessels,  and  thereby  withdrawing  the  blood  from 
the  brain. 

In  many  diseases  in  which  the  symptoms  point  to  a  disorder  of  the 
metabolism,  water  and  salt  solutions  are  advised.  Thus  gout  and 
rheumatism  are  frequently  treated  by  sending  the  patient  to  watering 
places,  on  the  theory  that  the  tissues  are  washed  out  thoroughly 
and  the  waste  products  thus  removed.  As  a  matter  of  fact,  the  more 
recent  work  in  this  direction  shows  that  large  quantities  of  water  and 
dilute  salt  solutions  have  little  or  no  effect  on  the  uric  acid  excretion, 
which  was  formerly  believed  to  be  much  diminished.  This  fact  does 
not  necessarily  involve  the  inference  that  the  treatment  is  erroneous, 
for  it  is  now  generally  recognized  that  gout  is  not  really  due  to  the 
failure  of  the  uric  acid  excretion.  INIany  cases  are  unquestionably 
benefited  by  the  springs,  although  it  may  be  questioned  how  much 
of  the  improvement  is  due  to  the  water  taken,  and  how  much  of  it 
ought  to  be  ascribed  to  the  changed  conditions  of  life. 

The  bath  treatment  has  been  recommended  for  numerous  diseases 
in  which  the  salt  and  water  could  not  possibly  have  any  beneficial 
action,  and  in  which  the  remedial  agent  is  the  climate,  and  perhaps 
the  faith  of  the  patient  in  the  water.  Belief  in  the  healing  power  of 
certain  natural  waters  is  one  of  the  most  ancient  of  all  therapeutic 
theories,  is  found  among  altogether  uncivilized  peoples,  and  has  been 
incorporated  in  many  religions.  It  is  not  to  be  wondered  at  that  in 
some  nervous  disorders  the  faith  of  the  patient  and  auto-suggestion 
perform  some  marvelous  "cures." 

In  obesity  the  drinking  of  some  waters,  such  as  those  of  Kissingen 
and  Homburg,  has  been  advised.  These  waters  contain  from  0.2-1.4 
per  cent,  sodium  chloride,  and  it  seems  very  doubtful  if  they  have  any 
effects  in  themselves;  many  hold  that  the  benefits  accruing  from  the 
treatment  are  really  due  to  the  hygienic  measures  followed,  and  that 
the  waters  play  only  an  insignificant  role. 

Salt  in  solid  form  or  in  strong  solution  is  used  occasionally  as  an 
emetic  in  cases  of  emergency,  as  in  poisoning,  and  generally  produces 
vomiting  rapidly,  owing  to  the  irritant  action  on  the  stomach.  In 
nitrate  of  silver  poisoning  it  arrests  the  corrosive  action  by  the  forma- 
tion of  the  insoluble  silver  chloride. 

Salt  solution  is  often  used  instead  of  water  in  enemata  and  when 
concentrated  possesses  an  irritant  action  on  the  bowel,  producing 
peristalsis.  Strong  solutions  are  sometimes  thrown  into  the  rectum 
to  destroy  thread  worms. 

Isotonic  salt  solutions  (0.6-0.9  per  cent.),  are  often  administered 
when  the  body  has  lost  much  fluid,  as  they  are  rapidly  absorbed  and 
are  devoid  of  irritant  action;  thus  in  haemorrhage  these  solutions 
are  injected  subcutaneously,  intravenously,  or  per  rectum.  A  rapid 
improvement  in  the  circulation  follows,  and  this  has  given  rise  to 
the  erroneous  opinion  that  such  saline  infusions  stimulate  the  heart 
directly  as  well  as  by  the  mechanical  effect  of  the  increase  in  the  fluids 
of  the  body;  this  theory  has  led  to  infusions  being  made  in  weakness 


512  SUBSTANCES  ACTING  AFTER  ABSORPTION 

of  tilt'  heart  from  other  causes  than  haemorrhage.  Some  of  the  symp- 
toms of  cholera  are  believed  to  be  due  to  the  loss  of  fluid,  and  these 
are  said  to  be  relieved  by  the  injection  of  salt  solutions,  though  the 
mortality  does  not  seem  materially  altered.  The  intravenous  and  sub- 
cutaneous injection  of  salt  solution  has  been  recommended  in  uraemia 
and  similar  intoxications,  with  the  idea  of  washing  out  the  poisons 
through  the  kidneys;  the  same  results  can  often  be  obtained  l)y  drink- 
ing large  quantities  of  water.  The  hypodermic  injection  of  large 
quantities  of  isotonic  salt  solution  is  said  by  Biernacki  to  have  effects 
which  only  pass  off  in  some  6-8  days  in  animals.  The  blood  is  at 
first  much  diluted,  but  afterward  becomes  very  concentrated  and  after 
a  few  days  a  considerable  number  of  the  red  cells  are  found  in  a 
state  of  disintegration,  and  the  haemoglobin  thus  liberated  is  dis- 
tributed through  the  plasma  until  it  is  finally  excreted  in  the  urine. 
The  animals  do  not  seem  to  sufi'er  from  the  treatment,  but  his  results 
indicate  that  the  injection  of  large  quantities  of  salt  solutions  is  by  no 
means  the  harmless  proceeding  which  it  is  generally  believed  to  be. 

The  istonic  salt  solution  ordinarily  employed  for  heemorrhage  and 
other  purposes  is  inferior  to  the  Ringer's  solution,^  which  contains  the 
other  salts  of  the  alkalies  in  approximately  the  proportions  in  which 
they  are  found  in  the  plasma;  for  excised  organs  live  for  many  hours  in 
this  balanced  solution,  while  they  lose  their  vitality  rapidly  in  an  istonic 
solution  of  sodium  chloride. 

Isotonic  salt  solutions  are  used  in  surgery  to  wash  out  the  peritoneal 
cavity,  which  would  be  injured  by  distilled  water. 

According  to  a  recent  view,  the  retention  of  sodium  chloride  in  the 
tissues  may  lead  to  the  retention  of  fluid  and  may  thus  tend  to  cause 
(cdema  and  dropsy.  These  conditions  have  therefore  been  treated 
by  a  diet  containing  a  low  proportion  of  salt,  and  in  a  certain  number 
of  cases  with  some  success.  It  is  still  doubtful,  however,  whether  the 
theory  is  correct,  and  the  improvement  may  \vAve  arisen  from  other 
factors  than  the  restriction  of  chlorides  in  the  food. 


Bibliography. 

Heidenhain.     Pfliiger's  Arch.,  xlix,  p.  209;  Ivi,  p.  579. 
Starling,  etc.     .loiirn.  of  Physiol.,  xvi,  xvii,  xviii,  xix. 
Cohnslcin.     Pfliigor's  Arch.,  lix,  Ixii,  Ixiii.     Virchow's  Arch.,  cxxxv,  p.  514. 
Mendel.     Jourii.  of  Physiol.,  xix,   p.  227. 
Orlow.     Pfliiger's  Arch.,  lix,  p.  170. 
V.  Limbeck.     Arch.  f.  cxp.  Path.  u.  Phanu.,  xxv,  p.  09. 
Dreser.     Ibid.,  xxix,  p.  303. 
Reichmann.     Ibid.,  xxiv,  p.  78. 
Munzer.     Ibid.,  xli,  p.  74. 

Loeb.     Amor.  Jourri.  of  Physiol.,  iii,  pp.  327,  383,  434;    Pfliiger's    Arch.,  Ixxxviii,  p. 
68;    xcvii,  p.  394. 

Heilncr.     Ztschr.  f.  Biol.,  xlvii,  p.  538. 

Bitlorf.     Deutsch.  Arch.  f.  klin.  Med.,  Ixxxix,  p.  485;    xciv,  p.  1. 

•  Ringer's  solution  suitable  for  mammals  contains  8.5  G.  NaCl,  0.3  G.  K("l.  0.2  G. 
NallGO.,  and  0.2  G.  raCi;  in  a  liter  of  distilled  water. 


POTASSIUM  SALTS  513 

Bunae.     Ztschr.  f.  Bioloj^iu,  xli,  ]).  484. 
Ludwig.     Ceutralbl.  f.  inn.  Med.,  1896,  Nos.  45  and  46. 
Wchcr.     Ergob.  d.  Phys.,  iii,  1,  p.  268.     (Mctal)olisni.) 

Loch,  Malhcws,  Zoelhoul,  Lillie,  etc.     Amer.   Journ.    of    Phy.siol.,    iii-xi    (antaKonistic 
action  of  salts). 

Feis.     Virchow's  Arch.,  cxxxviii,  p.  75. 

Biernacki.     Ztschr.  f.  klin.  Med.,  xix,  Suppl.,  p.  49. 

Straub.     Ztschr.  f.  Biologie,  xxxvii,  p.  527;    xxxviii,  p.  537. 

Magnus  u.  Gottlieb.     Arcli.  f.  exp.  Path.  u.  Pharm.,  xliv  and  xlv. 

Lcnhartz.     Deutsch.  Arch.  f.  kUn.  Med.,  Ixiv,  p.  189. 

Leonfacher.     Mittheil.  a.  d.  Grenzegebiete,  vi,  p.  321. 

Taijlor,  Frazer,  Edsall.     Pepper  Laboratory  Reports,  Philadelphia,  1900,  pp.  356,  368. 

Sollmann.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlvi,  p.  1. 


XXXVII.    POTASSIUM  SALTS. 

The  effects  of  potassium  in  the  organism  can  best  be  studied  by 
administering  the  chloride,  as  the  CI  ion  is  practically  devoid  of  action 
and  the  symptoms  induced  by  potassic  chloride  must  therefore  be  due 
either  to  the  "salt-action"  or  to  the  potassium.  The  salt-action  can 
be  discounted  by  comparing  the  symptoms  with  those  of  *an  isotonic 
solution  of  sodium  chloride,  and  when  this  is  done  it  is  found  that 
potassium  has  a  distinctly  poisonous  action,  which  is  chiefly  manifested 
in  depression  of  the  central  nervous  system  and  of  the  heart. 

In  the  frog  the  central  action  is  shown  by  the  spontaneous  move- 
ments becoming  weak  and  slowly  performed,  and  by  their  completely 
disappearing  much  earlier  than  in  sodium  chloride  experiments.  In 
mammals  the  chief  nervous  symptoms  are  great  muscular  weakness 
and  apathy.  The  respiration  becomes  rapid  and  labored,  probably 
from  the  anaemia  of  the  centre.  Mathisqn  states  that  potassium  first 
increases  the  activity  of  the  spinal  centres  and  then  paralyzes  them  in 
mammals,  but  this  is  concealed  by  the  depression  of  the  heart  when  the 
drug  is  injected  intravenously. 

The  depression  of  the  heart  is  shown  in  the  frog  by  weakness,  slow- 
ness and  irregularity  when  chloride  of  potassium  is  injected  subcu- 
taneously,  but  is  more  clearly  demonstrated  by  the  rapid  failure  of 
an  excised  heart  when  a  chloride  of  potassium  solution  is  perfused 
through  it.  An  isotonic  solution  of  common  salt  also  brings  the  heart 
to  standstill  after  a  time,  but  potassic  chloride  acts  very  much  more 
quickly,  and,  in  fact,  the  former  may  restore  the  heart  beat  after  it 
has  been  stopped  by  potassium,  which  proves  conclusively  that  the 
latter  has  a  specific  poisonous  action  in  addition  to  any  salt-action. 
Ringer,  however,  found  that  the  beat  of  the  frog's  heart  perfused  with 
a  solution  of  common  salt  was  not  so  satisfactory  as  that  of  one  per- 
fused with  the  same  solution  to  which  some  potassic  salt  had  been 
added,  probably  because  when  the  fluid  perfused  contains  no  potassium, 
some  of  the  salts  of  that  metal  diffuse  out  of  the  muscle  cells  and  this 
disturbs  the  ratio  between  the  potassium  and  sodium  which  is  necessary 
to  life. 

The  mammalian  heart  is  also  injured  by  the  action  of  potassium 
when  the  salt  is  injected  intravenously,  as  is  shown  by  weakness  and 
33 


514  srnsTANCEs  acting  after  absorption 

dilatation,  slowness  of  the  pulse,  heart  block,  and  finally  by  ventricular 
fii)rillation  not  infrequently;  the  l)lood-])ressure  falls  abruptly  from  this 
action  on  the  heart,  which  appears  to  be  a  direct  one  on  the  muscle,  the 
inhibitory  mechanism  not  being  involved.  The  poisonous  action  of 
potassium  on  the  heart  has  given  rise  to  exaggerated  apprehensions  of  the 
danger  of  using  its  salts  in  therapeutics,  and  it  may  therefore  be  noted 
that  potassium  has  no  efl^'ect  on  the  heart  when  given  by  the  stomach, 
and  that  very  much  larger  quantities  of  potassium  are  taken  daily  in 
the  food  by  thousands  of  persons  than  are  ever  prescribed  in  medicine. 
Hunge  estimates  the  amount  of  potassium  in  the  food  of  some  classes  at 
r)()-100  grms.  {\\~'^  oz.)  per  day.  Meltzer  has  recently  shown  that  the 
magnesium  salts  are  much  more  poisonous  than  those  of  potassium,  yet 
magnesium  sulphate  is  often  employed  in  doses  of  |-1  oz.  without 
deleterious  efl'ects.  The  absence  of  effects  from  the  potassium  ion  when 
the  salts  are  taken  by  the  mouth  is  due  to  their  rapid  excretion  in  the 
urine.  In  practical  therapeutics  the  potassium  salts  may  be  regarded 
as  equivalent  to  the  corresponding  sodium  ones  except  when  they 
are  injected  intravenously. 

The  failure  of  the  heart  is  the  cause  of  death  in  mammals  when 
potassium  salts  are  injected  into  a  vein,  the  respiration  and  the  reflexes 
often  persisting  for  a  few  seconds  afterwards.  When  potassium  salts  are 
injected  into  an  artery,  so  that  they  can  reach  the  peripheral  vessels 
before  the  heart,  they  cause  marked  ^•asoconstriction  with  an  abrupt 
rise  in  the  blood-pressure;  this  action  appears  to  be  a  direct  one  on  the 
walls  of  the  arterioles  for  the  most  part,  though  it  is  possible  that  this 
is  reinforced  by  stimulation  of  the  medullary  and  spinal  vasomotor 
centres  (Mathison). 

Potassium  has  some  action  on  muscle  in  the  frog,  the  contraction  secmin<i 
to  be  somewhat  greater  in  height,  though  shorter  in  length,  and  tliere  being 
less  tendenciy  to  contracture.  Muscle  exposed  in  a  solution  of  potassic  clilo- 
ridc  dies  very  much  sooner  than  in  an  isotonic  solution  of  sodium  chloride. 
Unstriated  muscle  suspended  in  a  solution  of  potassium  chloride  undergoes 
contraction,  wliicli  maj'  be  removed  h}^  replacing  tlie  jiotassium  witli 
sodium. 

Chloride  of  potassium  has  also  some  depressant  action  on  the  jjeripheral 
nerves,  for  they  lose  their  irritability  rapidly  when  they  arc  exposed  to  its 
solutions.  A  concentrated  solution  apjilied  to  an  exposed  nerve  causes  con- 
tractions of  the;  muscles  which  arc  supi)lied  by  it,  but  tliese  are  weaker  and 
last  a  nuich  sliorter  time  than  those  elicited  by  a  similar  solution  of  common 
salt.  This  is  explained  by  the  dei)ressant  action  of  tlie  potassium  opposing 
the  irritalion  which  it  induces  through  its  salt-action. 

The  abs()ri)tion  of  ])otassium  salts  is  followed  l)y  the  same  cliaiiges  in  tlic 
movements  of  tlie  fluids  of  the  body  as  have  been  described  in  the  case  of  sodium 
chloride  (page  507).  This  generally  results  in  diuresis  with  an  increase  in 
the  pota.ssium  and  the  .sodium  and  chloride  in  the  urine.  The  jKitassium  salts 
are  generally  credited  with  greater  diuretic  i)r<)perties  than  those  of  sodium. 
Strong  solutions  of  pota.ssic  chloride  are  said  to  lie  more  iiritaling  to  the 
stomach  and  also  in  the  subcutaneous  tis.sues,  than  tho.^e  of  .sodium  chloride; 
this  would  iiidicale  that  i)()tassium  has  a  specific  irritant  action  ajiart  from  its 
salt-action,  which  is  not  unlikely,  although  it  cannot  be  saiil  to  have  been 
deinonstratcil  sat  islactorilv  as  vet. 


AMMONIUM  515 


Bibliography. 

See  also  Sorliiim  Chloride. 

Bunge.     Pfli'iger's  Archiv,  iv,  p.  235;  Handbuch  dcr  physiol.  Chcm.,  p.  107. 

Martin.     Amer.  Journ.  of  Physiol.,  xi,  p.  370. 

Hold.     Arch.  f.  exp.  Path.,  liii,  p.  227. 

Ringer.     See  the  bibliography  given  under  Calcium. 

Brunton  and  Cash.     Phil.  Trans.  Roy.  Soc,  1884,  Part  1,  p.  197. 

Mathison.     Journ.  of  Physiol.,  xlii,  p.  471. 

Lithium,  Caesium,  Rubidium. 

In  regard  to  the  action  of  the  rarer  alkahes,  Lithium,  Caesium  and  Rubid- 
ium,^ comparatively  httle  is  known.  They  seem  to  have  some  eiTect  in  depres- 
sing the  spinal  cord  in  the  frog,  but  it  is  uncertain  whether  this  is,  like  the 
action  of  sodium  chloride,  merely  due  to  the  presence  of  large  quantities  of 
salts  in  the  body,  or  whether  they  have  a  specific  action  on  the  nerve  cells. 
Lithium  seems  to  have  some  further  depressant  action  on  the  motor  nerves, 
and  to  weaken  the  muscular  contraction.  It  acts  much  less  powerfully  on 
the  mammalian  heart  than  potassium,  but  has  some  effect  in  weakening  it. 
Its  chief  effects  are  exercised  in  the  alimentary  tract,  for  gastro-enteritis  and 
extravasations  of  blood  into  the  stomach  and  bowel  are  induced  by  its  sub- 
cutaneous or  intravenous  injection  and  these  are  the  cause  of  death  in  fatal 
poisoning  in  animals.  Such  violent  effects  are  less  easily  elicited  by  the  ad- 
ministration of  lithium  by  the  mouth,  though  vomiting  and  purging  have 
l)een  caused  in  animals  by  this  method  also,  and  disturbance  of  the  alimentary 
tract  has  sometimes  followed  from  lithium  treatment  in  man.  Some  of  the  lithium 
is  excreted  in  the  bowel,  and  in  this  respect  this  metal  appears  to  form  a  con- 
trast to  potassium  and  sodium  and  to  resemble  rather  the  group  of  alkaline 
earths.  Most  of  it  appears  in  the  urine,  however,  and  here  the  excretion  is 
slow,  for  traces  may  be  found  in  it  for  many  days  or  even  weeks  after  a  single 
administration. 

Rubidium  seems  to  act  on  the  frog's  heart  and  on  muscle  cells  in  much  the 
same  way  as  potassium.  It  is  slowly  excreted  by  the  kidneys;  traces  are  found 
also  in  the  fseces,  especially  if  diarrhoea  occurs,  as  is  not  infrequently  the  case. 

Csesium  resembles  lithium  in  causing  inflammatory  reactions  in  the  alimen- 
tary tract,  leading  to  vomiting  and  diarrhoea,  when  it  is  injected  hypoder- 
mically  or  when  large  doses  are  given  by  the  mouth.  It  is  partly  excreted  along 
the  alimentary  tract  in  mammals.  In  the  frog  it  induces  weakness  of  the 
muscles  and  paralysis. 

Bibliography. 

Dietrich  u.  Harnack.     Arch.  f.  exp.  Path.  u.  Pharm.,  xix,  p.  153. 

Brunton  and  Ca'ih.     Phil.  Trans.  Roy.  Soc,  1884,  p.  197. 

Blumenlhal.     Pfliiger's  Arch.,  Ixii,  p.  513. 

Winkler.     Ibid.,  Ixxi,  p.  395. 

Good.     Amer.  Journ.  Med.  Sciences,  cxxv,  p.  273.     (Lithium.) 

Berger.     Arch.  f.  exp.  Path.,  Iv,  p.  1. 

Hanford.     Amer.  Journ.  of  Physiol.,  ix,  p.  214.     (Cesium.) 

Mendel  and  Closson.     Ibid.,  xvi,  p.  147.    (Rubidium.) 

XXXVin.    AMMONIUM. 

Although  ammonium  is  not  a  metal,  its  behavior  in  the  body  resem- 
bles in  many  points  that  of  the  fixed  alkalies,  and  it  may  therefore 

'  The  still  rarer  metals  Yttrium,  Erbium,  Beryllium,  Didymium  and  Lanthanum  have 
scarcely  received  examination  except  at  the  hands  of  Brunton  and  Cash,  and  are  not  of 
sufficient  importance  to  require  further  mention  here. 


:)I('.  SUBSTANCES  ACTISd  AFTER  ABSORPTION 

host  1k'  studied  aloni;-  with  them.  The  solutions  of  ammonia  and  the 
,1,'as  itself  are  strongly  alkaline  and  therefore  powerful  irritants,  and  the 
general  action  of  the  ammonium  ion  can  be  determined  only  by  the 
examination  of  those  of  its  salts  in  which,  as  in  ammonium  chloride,  the 
effects  of  the  anion  can  be  neglected.  The  action  of  chloride  of  ammo- 
nium is  due  to  the  specific  action  of  the  base  and  to  the  salt-action. 

Action. — Its  most  striking  effect  is  the  stimulation  of  the  Central 
Nervous  System,  which  is  induced  when  it  is  injected  subcutaneously 
or  intravenously.  The  reflex  irritability  is  much  increased,  and  this 
may  be  followed  hy  tetanic  convulsions,  both  in  frogs  and  mammals. 
These  convulsions  persist  after  division  of  the  cervical  spinal  cord 
and  destruction  of  the  medulla  oblongata  and  brain,  and  are  evidently 
caused  by  changes  in  the  spinal  cord,  similar  to  those  met  with  in 
strychnine  poisoning.  The  medullary  centres  are  also  involved,  for 
the  respiration  very  often  ceases  for  a  moment,  and  then  becomes 
very  much  accelerated,  and  in  some  instances  deeper,  from  stimulation 
of  the  centre. 

The  blood-pressure  rises  from  contraction  of  the  peripheral  arte- 
rioles, induced  by  stimulation  of  the  vasomotor  centre,  while  the  heart 
is  sometimes  slowed  from  increased  activity  of  the  inhibitory  centre, 
but  is  said  to  be  accelerated  in  other  cases;  whether  this  arises  from 
action  on  the  cardiac  muscle  or  on  the  accelerator  centre  is  still 
unknown. 

During  the  convulsions  the  respiration  is  arrested  and  the  blood- 
pressure  becomes  extremely  high.  If  large  enough  ciuantities  be 
injected,  the  stimulation  is  followed  by  paralysis  of  the  central  ner\'ous 
system  and  the  animal  dies  of  asphyxia,  but  if  artificial  respiration 
be  carried  on,  it  recovers  rapidly,  from  the  salt  being  eliminated. 

In  the  frog  ammonium  chloride  tends  to  paralyze  the  terminations 
of  the  Motor  Nerves,  but  little  or  no  such  action  is  met  with  in  mam- 
mals. This  marked  curara-like  action  differentiates  the  ammonium 
tetanus  of  the  frog  from  that  seen  under  strychnine,  as  the  spasms 
last  a  shorter  time,  and  soon  become  weaker,  from  the  impulses  failing 
to  reach  the  muscles  through  the  depressed  terminations.  The  Muscles 
themselves  are  also  acted  on  by  ammonium  in  much  the  same  way  as 
by  potassium.  Ammonium  chloride  is  generally  credited  with  acting 
on  the  Secretions  of  the  stomach  and  of  the  bronchial  mucous  mem- 
brane, which  it  is  said  to  render  more  fluid  and  less  tenacious,  and  at 
the  same  time  to  increase  considerably.  It  may  also  have  some  effect 
in  relaxing  the  bronchial  muscle. 

Ammonium  salts  penetrate  most  cells  of  the  body  more  freely  than 
the  salts  of  the  fixed  alkalies,  and  solutions  of  ammonium  chloride  are 
therefore  absorbed  more  rai)i(lly  from  the  stomach  and  intestine  than 
those  of  sodium  or  potassium  chloride.  They  permeate  into  the  blood 
cells  with  still  greater  freedom,  and,  in  fact,  solutions  of  the  chloride 
of  annnonium  meet  with  little  more  resistance  in  entering  the  red- 
blood  corpuscles  than  does  distilled  water.  If  annnonium  be  combined 
with  a  non-permeating  ion  it  penetrates  the  bk)oil  cells  or  the  intestinal 


AMMONIUM  517 

epitheliinn  with  difficiilty,  however,  so  that  the  sulphate  of  ammonium 
is  sHu;htly  cathartic,  altliough  less  so  than  the  sulphates  of  the  fixed 
alkalies.  (See  Saline  Cathartics.)  The  epithelium  of  the  lungs  has  been 
stated  to  be  impermeable  by  the  ammonium  ion,  but  this  has  been 
disputed,  and  it  is  stated  that  ammonium  convulsions  may  be  caused 
in  animals  by  the  gas  absorbed  by  the  lungs  (McGuigan). 

AYhen  ammonium  salts  are  taken  by  the  mouth,  they  have  little  or 
no  tendency  to  cause  symptoms  from  either  the  central  nervous  system 
or  the  heart.  No  case  is  known  in  which  convulsive  attacks  could  be 
shown  to  be  due  to  the  direct  action  on  the  central  nervous  system  in 
man,  and  it  is  very  doubtful  whether  the  circulation  is  affected  at  all. 
In  some  cases  of  poisoning  with  ammonium  hydrate,  convulsions  have 
occurred,  but  these  seem  to  be  due  to  the  violent  irritation  caused  by 
the  strong  alkali. 

Excretion. — Some  of  the  ammonium  salts  are  excreted  unchanged 
in  the  urine,  while  other  are  changed  to  urea.  This  transformation, 
which  probably  takes  place  in  the  liver  chiefly,  proceeds  very  rapidly, 
.  so  that  considerable  quantities  of  some  salts  may  be  injected  slowly 
into  a  vein  without  inducing  any  symptoms  whatever.  In  the  herbi- 
vora,  urea  is  formed  whatever  salt  of  ammonia  is  injected,  but  in  the 
carni\ora  and  in  man  this  is  true  only  of  the  carbonate  and  the  salts 
which  are  oxidized  to  the  carbonate  in  the  body,  such  as  the  acetate 
and  citrate.  The  explanation  seems  to  be  that  in  the  herbivora  the 
abundant  fixed  alkali  of  the  blood  and  tissues  displaces  the  ammonium 
of  such  salts  as  the  chloride,  and  the  carbonate  of  ammonium  thus 
formed  is  changed  to  urea.  In  the  carnivora  and  man,  the  supply  of 
fixed  alkali  being  less  abundant,  the  ammonium  chloride  is  not  changed 
to  the  same  extent,  but  is  excreted  as  such  in  the  urine.  In  the  herbi- 
vora the  administration  of  ammonium  chloride  is  therefore  followed 
by  an  increased  elimination  in  the  urine  of  urea  and  of  the  chlorides 
of  sodium  and  potassium  which  are  formed  by  the  interchange;  at 
the  same  time  the  fixed  alkalies  of  the  blood  are  reduced  in  amount, 
and  this  ma}'  give  rise  to  serious  symptoms  (see  Acids).  In  the 
carnivora  and  man  chloride  of  ammonium  does  not  increase  the  urea 
appreciably,  but  is  excreted  as  such  in  the  urine. 

The  urine  is  often  increased  by  the  exhibition  of  ammonium  salts, 
but  not  always.  It  is  to  be  noted  that,  wdiile  the  alkaline  salts  of  the 
fixed  alkalies  render  the  urine  less  acid  or  even  alkaline,  ammonium 
salts  have  no  such  efi'ect,  because  they  are  excreted  as  urea  or  as 
neutral  salts. 

In  birds  and  reptiles  ammonia  is  apparently  excreted  as  uric  acid. 

The  Substituted  Ammonias  of  the  methane  series,  such  as  methylamine, 
and  some  of  those  of  the  aromatic  series  resemble  ammonium  in  their  general 
effects,  but  the  stimulation  of  the  central  nervous  system  is  not  often  so 
marked.  In  general  terms,  those  compounds  in  which  one  hydrogen  atom  is 
substituted,  tend  to  cause  greater  nervous  stimulation  than  those  in  which  two 
or  three  such  substitutions  ai'e  made,  while  tliis  action  is  again  more  promi- 
nent in  those  in  which  four  alkj'l  groups  are  combined  with  llie  nitrogen.     In 


518  SUBSTANCES  ACTING  AFTER  ABSORPTION 

addition,  most  of  these  compounds  seem  to  have  a  more  depressant  action  on 
the  central  nervous  system  afterward  than  ammonium,  and  they  all  tend  to 
weaken  and  eventually  to  paralyze  the  terminations  of  the  motor  nerves.  Some 
of  them  slow  the  heart  l)y  an  action  resembling  that  of  muscarine,  while  others 
act  on  the  peripheral  ganglia  like  nicotine. 

The  annnonium  bases  formed  from  the  natural  alkaloids  appear  to  have 
less  action  on  the  central  nervous  system,  but  act  like  curara  on  the  termina- 
tions of  the  motor  nerves. 

Preparations. 

Ammonii  Chloridum  (U.  S.  P.,  B.  P.)  (NH4CI),  0.5  G.  (7^  grs.);  B.  P.,  5-20 
grs.,  in  solution. 

Trochisci  Ammonii  Chloridi  (U.  S.  P.),  each  containing  0.1  G.  (2  grs.)  of 
ammonium  chloride  with  0.2  G.  (4  grs.)  of  liquorice  extract  and  some  syrup 
of  Tolu. 

Therapeutic  Uses.— The  chloride  is  prescribed  chiefly  for  its  effects 
on  the  respiratory  mucous  membranes,  and  is  a  very  common  con- 
stituent of  expectorant  mixtures  for  bronchitis  and  catarrh.  The 
lozenge  is  often  used  for  sore  throat,  and  chloride  of  ammonium  solu- 
tions are  occasionally  inhaled  or  sprayed  into  the  throat.  It  has  also 
been  prescribed  in  gastric  catarrh  with  benefit  in  some  cases,  but 
whether  this  is  due  to  its  acting  on  the  mucous  secretion  is  unknown. 

Ammonium  chloride  and  the  chloride  of  trimethylammonium  were 
at  one  time  advised  in  rheumatism,  but  have  proved  useless  in  this 
disease. 

Bibliography. 

Lange.     Arch.  f.  cxp.  Path.  u.  Pharm.,  ii,  p.  364. 

Feltz  et  Ritter.     Journ.  de  I'Anat.  et  de  la  Physiol.,  1874,  p.  326. 

Funke.     Pfliiger's  Arch.,  ix,  p.  416. 

Yourinsky.     Arch.  d.  Sciences  biolog.,  iii,  p.  260. 

Formanek.     Arch,  internat.  de  Pharmacodyn,  vii,  p.  229. 

McGuigan.     Journ.  of  Pharmacology,  iv,  p.  453. 

Schmiedeherg.     Arch.  f.  cxp.  Path,,  viii,  p.  1. 

Hallervorden.     Ibid.,  x,  p.  125. 

Coranda.     Ibid.,  xii,  p.  76. 

Knieriem.     Zeitschr.  f.  Biol.,  x,  p.  263. 

Marfori.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxiii,  p.  71. 

Rumpf  u.  Kleine.     Zts.  f.  Biol.,  xxxiv,  p.  65. 

Pohl  u.  Munzer.     Arch.  f.  exp.  Path.  u.  Pharm.,  xliii,  p.  28. 

Brunlon  and  Cash.     Phil.  Trans.  Roy.  Soc,  1884,  i,  p.  197. 

Nebellhau.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxvi,  p.  451. 

Dale.     Journ.  of  Pharmacol.,  vi. 


XXXDC.     IODIDES. 

Altliougli  the  iodides  have  been  more  largely  used  in  medicine  than 
any  of  the  other  salts  of  the  alkalies,  their  mode  of  action  is  still 
vvrai)ped  in  obscurity.  This  is  due  to  the  unsatisfactory  state  of  the 
pathology  of  the  diseases  in  which  they  are  used,  to  the  fact  that  the 
attention  of  investigators  has  been  drawn  to  the  symptoms  of  poison- 
ing rather  than  to  the  tlu'rapeutic  action,  and  also  to  the  fact  that  the 
elfects  seems  to  vary  very  considerably  not  only  in  dillVreiit  indi\  iduals, 
but  also  in  the  same  person  at  diti'crent  times. 


'  iOblDES  519 

Symptoms. — Large  quantities  of  the  iodides  cause  irritation  of  the 
stomach  from  their  salt-action  and  induce  nausea  and  vomiting,  more 
rarely  diarrhoea;  but  these  symptoms  are  quite  distinct  from  those 
known  as  lodism,  which  may  arise  from  comparatively  small  quantities, 
and  which  are  most  commonly  seen  when  the  remedy  has  been  ad- 
ministered repeatedly. 

The  commonest  symptom  of  iodism  is  catarrh  of  the  Respiratory 
Passages,  more  especially  of  the  nose,  which  betrays  itself  in  some 
swelling  and  discomfort  in  the  nasal  mucous  membrane,  in  a  profuse 
watery  secretion,  and  in  sneezing.  The  catarrh  spreads  upward  to 
the  conjunctiva,  which  often  becomes  swollen  and  congested,  and  to 
the  frontal  sinuses,  where  it  induces  a  feeling  of  dulness  or  violent 
headache;  it  also  progresses  downward  to  the  tonsils,  which  become 
swollen  and  inflamed  in  some  cases.  Still  lower  it  occasionally  causes 
some  swelling  and  oedema  or  small  ulcers  in  the  larynx,  and  has  thus 
caused  dyspnoea,  which  has  necessitated  tracheotomy,  or  very  rarely 
has  proved  fatal.  Bronchitis  has  also  been  observed  in  man,  with  a 
profuse  watery  secretion,  and  in  animals  oedema  of  the  lungs  and 
pleuritic  effusion  have  been  produced  by  the  injection  of  iodides.  Even 
small  quantities  injected  intravenously  increase  the  mucus  secreted  by 
the  bronchi. 

In  the  Mouth  iodism  is  often  betrayed  by  swelling  and  irritation  of 
the  throat  and  tonsils  and  by  salivation,  rarely  by  swelling  of  the 
salivary  glands.  The  stomach  is  seldom  affected,  the  appetite  gener- 
ally remaining  good,  but  in  some  persons  iodides  induce  nausea  and 
gastric  discomfort.  A  single  dose  of  iodide  increases  the  amount  of 
gastric  juice  and  prolongs  the  secretion  aroused  by  the  taste  of  food. 

Skin  Eruptions  of  different  forms  are  also  common  results  of  the 
administration  of  iodides,  but  are  less  liable  to  occur  in  the  beginning 
of  the  treatment  than  the  catarrh  of  the  respiratory  passages.  These 
eruptions  may  simulate  almost  all  known  skin  diseases,  but  the  most 
common  forms  are  erythematous  patches,  or  papular  eruptions,  which 
may  pass  into  pustules  or  into  larger  inflamed  areas.  Eczema,  bullse. 
pemphigus  and  purpura  arise  less  frequently  from  the  use  of  iodides. 
In  some  cases  a  more  or  less  defined  area  of  oedema  has  been  observed 
in  the  face. 

The  Secretion  of  Urine  is  generally  increased  by  the  administration 
of  iodides,  as  of  other  salts  of  the  alkalies,  though  they  seem  to  have 
no  specific  action  on  the  kidneys.  In  rare  cases  albuminuria  has  been 
observed,  and  some  irritation  of  the  bladder,  urethra  and  vagina  is 
said  to  have  been  induced  by  iodide  treatment,  but  these  statements 
require  confirmation. 

In  abnormal  conditions  of  the  thyroid  gland,  the  iodides  and  many 
other  iodine  compounds  often  give  rise  to  a  series  of  symptoms  which 
are  due  to  the  excessive  production  of  the  specific  secretion  of  the 
gland,  which  itself  contains  iodine;  these  symptoms  are  quite  distinct 
from  those  described  as  iodism  and  may  rather  be  referred  to  as 
thyroidism.     Among  these  symptoms  are  acceleration  and  palpitation 


520  SUBSTANCES  ACTING  AFTER  ABSORPTION 

of  tlu-  lu-art,  tremors,  nervousness,  sleeplessness  and  disorders  of  sen- 
sation, such  as  localized  anaesthesia  or  neural^nc  pains.  Sometimes  • 
some  fever  or  accelerated  metabolism  leading  to  loss  of  weight  has 
occurred,  and  occasionally  extreme  emaciation  and  cachexia  with 
mental  depression,  which  only  abated  slowly  on  the  abandonment  of 
the  treatment,  or  which  in  rare  cases  were  permanent. 

In  many  instances  small  doses  of  iodide  may  be  given  repeatedly 
without  any  noticeable  disturbance,  but  in  others  the  smallest  (|uan- 
tity  (0.2  G.)  induces  severe  poisoning.  Some  authorities  consider  that 
these  small  doses  are  more  liable  to  cause  iodism  than  larger  ones, 
but  this  may  be  doubted,  as  the  action  of  the  drug  is  so  capricious 
that  the  statistics  of  different  observers  show  great  discrepancies,  even 
when  ai)proximately  the  same  dose  has  been  given.  Thus,  Ilashmd, 
treating  patients  with  at  first  3  G.  (45  grs.)  and  then  5  G.  (80  grs.) 
daily,  observed  iodism  in  only  12  per  cent,  of  his  cases  during  the  first 
few  days,  while  others  have  found  iodism  induced  in  GO  per  cent,  of 
their  cases  after  a  single  dose  of  3  G.  An  attempt  has  been  made  to 
explain  these  discrepancies  by  supposing  that  iodism  is  only  producetl 
by  impure  iodides,  but  this  is  not  correct,  for  it  has  been  observed  in 
numerous  cases  in  which  the  drug  was  absolutely  pure.  Among  other 
conditions  which  favor  the  onset  of  symptoms  is  a  slow  excretion  of 
the  iodide  such  as  is  observed  in  some  forms  of  renal  irritation. 
Children  seem  less  liable  to  sufler  from  the  iodides  than  adults.  The 
dose  administered  has,  of  course,  some  relation  to  the  onset  of  symp- 
toms; thus,  very  large  doses  are  more  likely  to  induce  them  than  very 
small  ones,  but  it  seems  that  a  tolerance  is  soon  established  in  some 
cases,  for  after  iodism  has  been  induced,  and  the  daily  dose  lessened 
accordingly,  it  is  sometimes  found  that  it  may  be  gradually  increased 
until  a  quantity  considerably  greater  than  that  originally  given  may 
!)e  taken  witii  impunity.  In  other  instances,  a  definite  quantity  nia\- 
be  given  for  a  long  time  without  inducing  symptoms,  but  these  may 
suddenly  set  in  without  any  apparent  change  in  the  treatment  and 
without  any  a])preciable  cause.  Very  often  it  is  found  that  the  symji- 
toms  disappear  while  the  treatment  is  continued,  and  recovery  in\ar- 
iably  sets  in  when  the  drug  is  abandoned.  The  iodides  all  induce 
iodism,  the  symi)toms  being  apparently  unaffected  by  the  basic  ion. 
The  condition  is  seldom  dangerous,  but  a  few  cases  are  recorded  in 
which  aniema  of  the  larynx  resvdted  and  proved  fatal. 

The  iodides  are  not  Absorbed  from  watery  solutions  ai)i)lied  to  the 
skin,  l)ut  are  rapidly  taken  up  by  all  the  mucous  mem])ranes.  WhiMi 
given  by  the  mouth  they  are  ai)sorbe(l  unchanged  by  the  stomach  and 
intestine,  and  appear  in  the  secretions  within  5  10  minutes.  The 
greater  j)art  of  the  iodide  is  Excreted  in  the  urine,  in  which  it  appears 
as  sahs.  Some  escapes  l)y  the  saH\ary  glands,  however,  and  small 
(|iiaiititics  are  excreted  by  the  stomach  as  hydriodic  acid  and  sonic- 
times  as  free  iodine;  iodide  has  also  been  found  in  the  tears,  perspira- 
tion, milk,  sebum,  and  in  the  secretion  of  the  nasal  mucous  membranes. 
More  iodide  is  lonnd  in  the  blood  than  in  an\   of  ihc  fixed  tissues;  the 


IODIDES.  521 

skin  is  also  rich  in  iodide,  while  the  hnigs,  kidneys  and  lymph  glands 
contain  smaller  quantities;  the  brain  and  fatty  tissues  have  merely 
traces;  diseased  organs  are  said  to  take  up  more  than  sound  ones. 
Iodides  are  much  more  rapidly  excreted  than  bromides,  for  ()5-S()  per 
cent,  of  the  iodide  appears  in  the  urine  within  24  hours  after  its  ad- 
ministration, and  no  iodide  reaction  is  obtained  from  any  of  the  secre- 
tions a  week  after  the  treatment  has  ceased.  Some  of  the  iodide  does 
not  appear  in  the  urine,  however,  and  its  fate  in  the  body  has  not  been 
very  clearly  traced.  Difl'erent  individuals  vary  in  the  amount  that  thus 
disappears,  Avhich  seems  to  be  fairly  constant  for  each  person;  thus  one 
patient  receiving  0.5  G.  of  potassium  iodide  may  retain  0.1  G.,  while 
another  after  the  same  dose  may  retain  0.2  G.  or  more,  the  same 
proportions  appearing  on  different  occasions. 

The  greater  part  of  the  iodide  administered  therefore  passes  through 
the  tissues  and  is  excreted  in  the  urine  in  the  form  of  salts.  Some  of 
the  iodide  undergoes  decomposition  in  the  body,  however,  for  free 
iodine  has  been  found  in  the  stomach,  and  an  organic  compound  of 
iodine  exists  in  the  hair  and  in  Aarious  internal  organs  after  iodide 
treatment.  The  successful  treatment  of  goitre  with  iodide  of  potassium 
is  also  a  strong  argument  in  favor  of  the  presence  of  free  iodine,  and  the 
iodine  of  the  thyroid  glands  has  been  shown  to  be  increased  by  potassic 
iodide.  When  iodine  is  thus  liberated  in  the  body,  it  does  not  circulate 
as  such,  but  at  once  combines  with  the  proteins,  and  its  presence  can  no 
longer  be  demonstrated  by  the  ordinary  tests. 

The  formation  of  free  iodine  from  iodides  (wliich  is,  of  course,  quite  dis- 
tinct from  their  dissociation  into  potassium  and  iodide  ions)  has  been  the 
subject  of  several  ingenious  theories,  none  of  which  have  been  estabHshed  and 
which  are  now  chiefly  of  historical  interest  and  need  not  be  entered  on  here. 

It  is  often  said  to  be  set  free  along  the  mucous  membrane  of  the  respiratory 
passages  and  in  the  skin;  and  in  this  way  the  corj^za  of  the  former,  and  the 
eruptions  on  the  latter  are  expUiined.  It  must  be  noted  that  free  iodine  has 
not  3^et  been  clearly  demonstrated  on  either  of  these  surfaces,  and  that  the 
theor}^  has  been  formulated  only  to  explain  the  sjanptoms  of  iodism.  Iodides 
have  been  found  in  the  nasal  secretion,  saliva  and  perspiration,  but  no  free 
iodine. 

The  central  nervous  system  and  the  circulation  scarcely  seem  to  be  affected 
by  iodides.  Very  large  quantities  of  potassic  iodide  injected  into  a  vein  are 
found  to  weaken  and  paralj'ze  the  heart  in  animals,  but  do  not  seem  to  be 
more  poisonous  than  other  potassium  salts,  and  depression  of  the  central  nervous 
system  may  also  be  elicited  in  the  same  way  by  the  potassium  action.  Barbera 
states  that  very  large  quantities  of  iodides  paralyze  tlie  depressor  nerve  termina- 
tions in  the  medulla  oblongata  and  weaken  the  peripheral  inhibitory  mechanism 
of  the  heart,  while  Hunt  found  the  accelerator  fibres  less  easily  fatigued  after 
iodide.  The  metabolism  of  the  body  seems  little  affected  bj^  iodides  in  most 
cases,  but  a  further  examination  of  the  excretions  of  patients  who  lose  weight 
under  the  treatment  is  desirable.  Fatty  degeneration  of  the  liver  is  stated  to 
occur  in  some  animals.  The  action  of  the  iodides  in  therapeutics  has  been 
ascribed  by  some  authors  to  their  rendering  the  movement  of  the  leucocytes 
(diapedesis)  more  active,  but  no  satisfactory  evidence  has  been  adduced  in 
support  of  this.  Another  view  is  that  the  autolysis  is  increased,  and  Kepinow 
has  observed  that  iodide  has  this  effect  in  the  hver  when  it  is  injected  uitra- 
venousl}'  during  life;  added  to  the  minced  liver  iodide  had  no  such  effect,  but 


ry22  SUBSTANCES  ACTING  AFTER  ABSORPTION 

iodine  accelerated  the  autolysis,  and  he  concludes  that  iodine  is  Uberated  from 
the  iodides  in  the  living  body.  Solutions  of  iodide  of  sodium  are  found  to  be 
more  poisonous  to  muscle,  cilia  and  unicellular  organisms  exposed  to  them  than 
are  similar  solutions  of  the  chloride  or  bromide,  so  that  the  iodide  ion  appears 
to  be  more  fatal  to  protoplasm  than  the  bromide  and  chloride  ion,  while  it  is 
less  poisonous  than  the  fluoride.  In  the  frog  stiffness  and  awkwardness  in  the 
movements  are  elicited  by  comparatively  small  doses  of  iodide  of  sodium  and 
these  symptoms  have  been  shown  to  be  due  to  rigor  mortis  occurring  in  the 
muscles. 

The  rapid  elimination  of  iodide  by  the  kidney  necessitates  frequent 
large  doses  if  the  action  is  to  be  maintained,  and  these  large  doses  in 
turn  tend  to  induce  iodism.  An  attempt  has  therefore  been  made  to 
introduce  iodine  combinations  which  are  slowly  decomposed  in  the 
tissues  and  thus  free  iodide  continuously'.  For  this  purpose  protein 
compounds  with  iodine  (Eigon,  lodolen,  etc.),  have  not  proved  successful, 
as  they  tend  to  free  the  iodine  in  the  alimentary  tract  and  the  resulting 
iodide  is  eliminated  almost  as  quickly  as  when  inorganic  iodide  is  ad- 
ministered. Combinations  of  iodine  with  oil  (lodipin)  or  with  fatty 
acids  {Sajodiii)  are  better  adapted  for  this  purpose  as  they  are  absorbed, 
stored  in  the  fat  depots  of  the  body  and  gradually  decomposed  with 
the  liberation  of  iodides.  No  iodine  is  found  in  the  urine  in  the  first 
hour  after  the  administration  of  these  organic  compounds  and  the 
maximum  excretion  takes  place  after  ten  hours;  the  iodide  reaction 
disappears  from  the  urine  after  84  hours. 

Preparations. 

PoTASSii  loDmuM  (U.  S.  p.,  B.  P.)   (KI),  0.5  G.  (7^  grs.);   B.  P.,  5-20  grs. 

SoDii  loDiDUM  (U.  S.  P.,  B.  P.)  (Nal),  0.5  G.  (7^  grs.);  B.  P.,  5-20  grs. 

The  iodides  form  colorless  crystals  when  pure,  a  j'ellowish  tint  indicating 
the  presence  of  free  iodine.  They  are  very  soluble  in  water,  less  so  in  alcohol, 
and  are  always  prescribed  in  watery  solutions,  and  often  along  with  carbo- 
nate of  sodium  or  potassium,  in  order  to  prevent  decomposition  as  far  as  possible. 
The  iodide  of  potassium  is  the  one  most  frequently  used  and  is  less  liable  to 
contain  free  iodine  than  the  others,  but  iodide  of  sodium  is  preferred  by  some; 
the  dose  often  has  to  be  much  increased  beyond  that  given  above.  The  iodide 
of  ammonium  is  said  to  b(!  more  liable  to  cause  skin  eruptions  and  disturb- 
ance of  the  digestion  than  the  others.  Some  iodide  effects  may  also  be  ob- 
tained bj''  the  use  of  iodide  of  lead  or  mercury,  but  here  they  are  complicated 
by  the  action  of  the  metal,  and  these  will  be  discussed  along  witli  the  other 
salts  of  lead  and  mercury.  The  external  application  of  iodides  is  not  attended 
by  any  general  effect,  though  some  irritation  may  be  induced  by  iodine  being 
liberated  by  the  decomposition  of  the  fats;  small  quantities  of  iodine  are  ab- 
sorbed and  changed  to  iodides  in  the  tissues. 

lodipin  (unofficial)  is  an  iodine  addition  product  of  sesame  oil  and  forms  a 
ycillow  oily  liquid  with  an  oily  taste.  It  is  prepared  in  two  strengths  containing 
10  per  cent,  and  25  per  cent,  of  iodin,  respectivel}^  Dose  4-8  c.c.  (1-2  drs.)  of 
iodipin  10  per  cent.  Hj^podermically  2-G  c.c.  (30-90  mins.)  of  ioilipin  25  per 
cent. 

Snjodin  (unofficial),  (C2iH42lCOO)2Ca,  the  monoiodobehenate  of  calcium  is  a 
colorless  and  tasteless  powtlcr  insoluble  in  water.  Dose,  1-3  G.  (15-45  grs.)  daily. 

Therapeutic  Uses. — The  iodides  arc  used  \ery  extciisivi'ly  in  the 
treatniciit  of  tcrtiarx'  syi)liilis,  in  wliicli  they  lia\t'  proxcd  in\ahial)lc. 


IODIDES  523 

They  have  also  been  administered  in  the  earher  stages  of  the  disease, 
but "ha^•e  i)ro\ed  to  be  of  httle  service  here.  In  syi)hihtic  bone  disease 
and  ulcers,  and  in  the  gunnnata  of  the  brain  and  other  internal  organs, 
however,  a  remarkable  impro\^ement  very  often  occurs  after  the  iodide 
treatment  has  been  adopted.  The  iodide  of  potassium  or  of  sodium 
is  almost  invariably  used,  and  is  given  in  as  large  doses  as  the  patient 
can  bear,  often  up  to  5  G.  (75  grs.)  daily.  The  iodide  is  often  prescribed 
along  with  mercury,  and  this  combination  is  found  more  efficient  than 
the  iodide  alone.  In  actinomycosis  iodide  treatment  has  proved  of 
value,  and  in  a  rare  infection  known  as  sporotrichosis,  which  arises  from 
a  fungus  nearly  related  to  actinomyces,  Bloch  states  that  the  efl'ects 
are  even  more  striking  than  in  tertiary  syphilis. 

In  syphilis  and  in  these  other  diseases,  the  iodide  does  not  act  as  a 
parasiticide;  the  spirochajta  of  syphilis,  for  example,  is  not  killed  by 
the  application  of  iodide  of  potassium  to  a  syphilitic  lesion,  and  the 
fungus  of  sporotrichosis  grows  readily  in  a  culture  medium  containing 
high  concentrations  of  iodide.  The  specific  effects  of  iodide  in  tertiary 
syphilis  are  exerted  not  on  the  parasite  but  upon  the  tissues  in  which 
it  lives  and  which  have  reacted  to  its  presence  by  the  formation  of 
tumors;  these  lowly  organized  tumors  dissolve  under  the  action  of 
iodides,  while  the  parasite  remains  unaft'ected,  but  is  now  more  readily 
accessible  to  the  parasiticide  drugs,  mercury  and  arsenic.  It  is  im- 
portant to  recognize  that  iodide  does  not  destroy  the  cause  of  the 
infection  but  only  removes  some  of  the  results. 

It  is  unknown  how  iodide  removes  the  gummatous  tissue;  Loeb 
states  that  iodide  accumulates  in  glands  infected  with  syphilis  in  greater 
concentration  than  elsewhere  in  the  body  and  that  iodine  exists  in 
organic  combination  there.  Kepinow  found  that  iodide  injected  intra- 
venously in  animals  accelerates  the  autolysis  of  the  liver,  and  an 
analogous  observation  has  been  made  by  Jobling  and  Petersen,  who 
found  that  serum  no  longer  inhibits  the  trypsin  action  in  the  presence 
of  iodides;  it  is  possible  that  it  similarly  promotes  the  autolytic  solution 
of  the  gumma. 

In  many  diseases  which  are  not  directly  attributed  to  syphilis, 
but  in  which  there  is  a  history  of  syphilis,  iodides  are  of  value;  thus, 
neuralgia  and  other  nervous  disturbances  are  often  relieved  by  them 
in  persons  of  a  syphilitic  taiiit,  and  in  fact,  improvement  is  often 
observed  in  the  most  diverse  conditions  in  persons  who  have  formerly 
suffered  from  this  complaint. 

Another  series  of  symptoms,  or  of  diseases,  which  is  often  treated 
with  iodides  is  rheumatism  in  its  various  manifestations.  The  treat- 
ment is  of  little  value  in  acute  rheumatism,  and  in  fact,  often  fails  in 
the  chronic  disease,  but  is  occasionally  attended  with  improvement, 
although  the  exact  conditions  in  which  this  occurs  are  still  unknown. 

The  iodides  have  long  enjoyed  some  reputation  in  the  treatment  of 
goitre,  but  the  thyroid  extract  has  proved  much  sujjerior  to  them  and 
promises  to  supplant  them  entirely,  as  their  effects  are  due  to  their 
action  on  the  thvroid  secretion.       The  same  may  be  said  regarding 


524  SUBSTANCES  ACTING  AFTER  ABSORPTION 

tlioir  use  in  obesity,  which  was  found  to  be  successful  in  some  cases, 
presumal)ly  of  thyroid  insufficiency.  When  thyroid  insufficiency  is  (hie 
to  tlie  absence  of  io(Une,  while  the  gland  cells  are  capal)le  of  normal 
action,  iodides  and  iodine  give  good  results;  but  when  the  symptoms 
arise  from  absence  or  atrophy  of  the  secretory  cells,  iodides  are  valueless, 
and  relief  is  given  only  by  the  administration  of  the  specific  secretion. 
(See  Thyroid  Extract.') 

Some  skin  eruptions  have  been  found  to  be  benefited  by  the  iodide 
treatment  even  when  no  suspicion  of  syphilis  could  be  entertained. 

The  success  attending  the  treatment  of  goitre  with  iodides  seems  to 
have  been  the  basis  of  their  use  in  cases  of  enlarged  lymphatic  glands, 
scrofula,  and  lupus,  but  here  the  results  are  very  doubtful,  although 
some  authorities  allege  that  the  iodide  treatment  is  of  \alue.  There 
is  a  general  consensus  of  opinion  that  the  old  treatment  of  malignant 
tumors,  such  as  cancer  and  sarcoma,  with  iodides  is  hopeless.  Iodide  is 
said  to  accumulate  in  tuberculous  glands  (Loeb)  and  also  in  cancerous 
and  sarcomatous  tumors  in  greater  concentration  than  in  the  other 
tissues. 

These  salts  are  sometimes  credited  with  promoting  the  absorption 
of  serous  effusions,  and  the  removal  of  hypertrophy-  of  connective 
tissue  in  the  body,  as  in  the  various  forms  of  sclerosis  and  cirrhosis. 
Their  efficacy  in  removing  the  syphilitic  gumma  was  evidently  the  origin 
of  their  use  here,  but  while  the  resolution  of  gummata  under  the 
iodides  is  beyond  question,  no  satisfactory  evidence  of  improvement 
in  these  non-syphilitic  affections  is  available. 

Aneurism  and  arteriosclerosis  have  often  l)een  treated  with  iodide, 
and  improvement  is  undoubtedly  observed  in  some  cases,  in  which 
there  is  probably  a  syphilitic  taint;  but  there  seems  no  reason  to  sup- 
pose that  the  iodides  have  any  special  action  on  the  vessels  apart  from 
their  action  on  poorly  organized  tissue,  such  as  is  formed  in  syphilitic 
infection,  for  no  change  in  the  heart,  pulse  or  blood-pressure  can  be 
observed  even  after  prolonged  treatment.^ 

Iodides  are  often  prescribed  along  with  other  remedies  in  expecto- 
rant mixtures,  the  object  being  to  render  the  bronchial  mucus  more 
watery  and  less  tenacious,  and  thus  to  facilitate  its  removal.  In  some 
cases  of  asthma  they  have  been  found  of  value,  perhaps  from  the 
same  action,  for  they  do  not  appear  to  affect  the  bronchial  nuiscles. 

iodide  of  potassium  is  generally  prescribed  in  chronic  iwisoning 
from  lead  or  mercury,  antl  is  believed  to  hasten  the  elimination  of 
these  metals,  although  it  has  not  been  shown  that  it  is  of  more  value 
here  than  other  salts,  such  as  the  chlorides  and  bromides.  The  belief 
in  the  efficacy  of  the  iodides  in  mercury  poisoning  has  suggested  that 
they  act  in  tertiary  syphilis  only  by  aiding  in  the  mobilization  of  the 
mercury  stored  in  the  tissues  from  the  treatment  of  the  earlier  stages, 
lint  this  is  incorrect,  for  the  iodides  are  of  value  in  cases  of  tertiary 

'  The  supposi-d  action  in  arteriosclerosis  lias  sometimes  been  ascribed  to  iodides  lessen- 
ing th<?  viscosity  of  the  blood;  but  the  experiments  on  which  this  explanation  is  based 
;iri'  not   eoMviiicinn. 


IODINE 


r^'^r^ 


syphilis  in  wliicli  mercury  has  not  hcen  previously  used.  It  is  stated 
that  when  iodide  is  given  along  with  mercury,  the  latter  does  not 
accumulate  in  the  li\er,  but  the  statement  requires  confirmation. 

Finally,  iodide  of  potassium  is  sometimes  added  to  other  drugs  in 
cases  of  malingering,  or  in  which  it  is  suspected  that  the  patient  is 
not  taking  the  remedy  as  directed.  If  the  iodide  is  swallowed  it  can 
he  detected  in  the  urine  by  the  addition  of  a  few  drops  of  chlorine 
water  and  of  starch  solution,  which  assumes  the  well-known  blue  color. 

Iodides  have  to  be  used  with  care  in  cases  of  pulmonary  phthisis, 
in  which  they  often  increase  the  cough  and  expectoration,  and  in  some 
cases,  it  is  alleged,  cause  haemoptysis.  Children  have  sometimes  been 
found  to  suffer  from  iodism  from  being  nursed  by  a  person  under  iodide 
treatment. 

Iodism  very  often  proves  a  disagreeable  accompaniment  of  the 
treatment,  and  is  sometimes  so  severe  as  to  preclude  the  use  of  the 
salts,  so  that  many  attempts  have  been  made  to  discover  some  expe- 
dient by  which  these  symptoms  may  be  avoided,  Init  as  yet  no  success 
has  been  obtained.  Iodism  occurs  less  readily  under  the  organic 
preparations  iodipin  and  sajodin,  but  it  is  not  yet  satisfactorily 
established  that  the  specific  action  in  syphilis  is  induced  as  certainly 
by  these  as  by  the  inorganic  iodides;  in  grave  cases  the  latter  should 
certainly  be  employed  in  preference. 

Bibliography. 

Blum.     Miinch.  med.  Woch.,  1898,  pp.  231  and  267. 

Binz.  Virchow's  Arch.,  Ixii,  p.  124;  Arch.  f.  cxp.  Path.  ii.  Phann.,  viii,  p.  320;  xiii, 
p.  139;  xxxiv,  p.   185. 

Boehm  u.  Berg.     Arch.  f.  exp.  Path.  u.  Pharm.,  v,  p.  329. 

Hogycs.     Ibid.,  x,  p.  250. 

Rohmann  u.  Malachowski.     Therap.  Monats.,  1889,  p.  301. 

Kuh.     Zeitschr.  f.  Biologic,  N.  F.,  v,  p.  460. 

Loeh.     Arch.  f.  exp.  Path.  u.  Pharm.,  Ivi,  pp.  314,  320;    Ixix,  p.  108. 

Feigl.     Biochem.  Ztschr.,  viii,  p.  467. 

Annuschat.     Arch.  f.  exp.  Path.  u.  Pharm.,  x,  p.  261. 

Anten.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlviii,  p.  331. 

Stockman  and  Charteris.  Journ.  of  Physiol.,  xxvi,  p.  277;  Brit.  Med.  Jourii.,  Nov. 
23,  1901. 

Takemura.     Zeitschr.  f.  phys.  Chem.,  Ixxii,  p.  78. 

Block.     Therap.  Monats.,  1910,  p.  24. 

Kepinow.     Biochem.  Zeitschr.,  xxxvii,  p.  238. 

Blumenthal  and  Oppenheim.     Ibid.,  xxxvi,  p.  291. 

Broking.     Zeitschr.  f.  exp.  Path.,  viii,  p.  125. 

McLean.     Therap.  Research  Committee,  Amer.  Med.  Assoc,  1912,  p.  130. 

Jobling  and  Petersen.     Journ.  Amer.  Med.  Assoc,  1914,  ii,  p.  1930. 

XL.    IODINE. 

Iodine  possesses  a  local  irritant  action  similar  to,  though  less  intense 
than,  that  of  chlorine  and  bromine  (p.  166).  It  is  much  less  volatile, 
and  therefore  comes  into  contact  with  the  tissues  more  slowly  than 
these,  but  the  chemical  change  is  analogous,  and  iodides  and  protein 
compounds  result. 


526  SUBSTANCES  ACTING  AFTER  ABSORPTION 

Action. — Wlien  applied  to  tlie  Skin,  it  dyes  it  a  yellow-brown  or 
dark  hrowii  color,  and  acts  as  an  irritant,  producing  a  sensation  of 
heat  and  itchinjj;.  In  very  concentrated  solution  or  in  the  solid  form 
it  may  cause  blistering  or  even  corrosion,  but  it  acts  much  more  slowly 
than  most  other  irritants,  and  at  the  same  time  the  irritation  is  more 
prolonged.  It  penetrates  into  the  deeper  layers  of  the  skin,  and  small 
quantities  are  absorbed. 

The  Mucous  Membranes  are  more  strongly  afi'ected  l)y  contact  with 
it;  thus  when  its  vapor  is  inhaled  for  some  time,  smarting,  swelling 
and  increased  secretion  is  caused  in  the  nasal  mucous  membranes,  con- 
junctiva, throat  and  lower  respiratory  passages,  resembling  exactly  the 
symptoms  known  as  iodism.  In  the  stomach  small  quantities  may 
cause  slight  irritation  and  improved  appetite,  but  as  a  general  rule 
nausea,  discomfort  and  vomiting  follow  its  administration  in  any  save 
the  most  minute  doses,  and  occasionally  diarrhoea  has  been  observed 
after  it  from  irritation  of  the  bowel.  In  cases  of  poisoning,  the  irri- 
tation of  the  alimentary  canal  may  prove  fatal  by  inducing  collapse 
and  failure  of  the  heart  and  respiration,  and  iodine  may  be  recognized 
in  the  vomited  matter  and  in  the  stools. 

Solutions  of  iodine  Injected  Subcutaneously  or  into  tumors  or  cysts, 
a  common  method  of  treatment  formerly,  cause  intense  pain  and  irri- 
tation which  may  induce  collapse  and  which  have  been  followed  in 
some  instances  by  suppuration  and  gangrene. 

Iodine  is  Absorbed  in  the  form  of  iodides,  and  perhaps  in  com])i- 
nation  with  proteins.  Its  fate  in  the  body  is  precisely  similar  to  that 
of  the  iodides — it  is  excreted  in  the  form  of  iodides,  chiefly  by  the  kid- 
neys, to  a  less  extent  in  the  saliva,  perspiration,  milk  and  secretions 
of  the  respiratory  passages.  The  administration  of  iodine  leads  to  an 
increase  in  the  iodine  of  the  thyroid  gland. 

Small  quantities  of  iodine  may  be  given  internally  to  many  persons 
without  eliciting  any  symptoms  except  those  which  are  clearly  due  to 
the  local  action.  Repeated  doses,  however,  sometimes  cause  symp- 
toms resembling  those  observed  after  iodides  (Iodism),  although  these 
have  been  much  less  often  induced  by  iodine,  which  is  comj)aratively 
seldom  administered  internally.  ]\Iany  other  symptoms  which  have 
been  observed  under  iodine  treatment,  obviously  arise  from  the  excessive 
activity  of  the  thyroid  gland,  and  are  especially  noticeable  in  goitre. 

Some  Cases  of  Poisoning  from  the  injection  of  large  quantities  of 
iodine  into  cysts  have  been  recorded.  In  Rose's  well-known  case,  the 
chief  symptoms  were  thirst,  constant  vomiting  (the  vomited  matter 
containing  iodine)  cyanosis  and  coldness  of  the  skin,  a  small,  weak 
pulse,  anuria  and  skin  eruptions  after  a  few  days;  and  death  occurred 
on  the  tenth  day.  In  such  cases  of  ])oisoning  in  man  the  mucous 
membrane  of  the  stomach  and  intestine  has  been  found  swollen  and 
loosened,  and  in  animals  fatty  degeneration  of  the  lixcr,  heart,  and 
kidney  has  been  described. 

Injected  into  the  \('ins  of  animals,  iodine  causes  (edema  of  the 
lungs,  wliieli  \-.  ZeissI  considers  to  be  due  in  part  to  changes  in  the 
left  \('ntricle,  in  part  to  contraction  of  the  pulmonary  arterioles. 


THY  HO  1 1)  GLAND  527 


Preparations. 

lodum  (U.  S.  P.,  B.  P.),  iodine,  is  not  used  in  therapeutics. 

Tinctura  lodi  (U.  S.  P.),  7  per  cent.,  0.1  c.c.  (1|  mins.). 

Liquor  lodi  Compositus  (U.  S.  P.),  Lugol's  Solution,  contains  5  per  cent,  dis- 
solved in  10  per  cent,  potassium  iodide  solution.    0.2  c.c.  (3  mins.). 

Unguentum  lodi  (U.  S.  P.,  B.  P.),  4  per  cent. 

Tinctura  lodi  Foriis  (B.  P.),  Iodine  Liniment,  about  10  per  cent,  of  iodine 
dis.solved  in  alcohol  with  potassium  iodide. 

Tincture  lodi  Mitis  {B.  P.),  2|  per  cent.,  2-5  mins. 

Therapeutic  Uses. — Iodine  has  been  used  internally  in  a  variety  of 
chronic  conditions,  such  as  syphilis  and  goitre,  and  in  tubercular 
disease  of  the  glands,  bones  and  other  organs,  but  it  has  been  almost 
entirely  superseded  by  the  iodides,  and  in  goitre  by  the  thyroid  prepara- 
tions. 

It  has  been  applied  locally  by  painting  on  the  skin  in  a  variety  of 
chronic  inflammatory  processes,  such  as  tubercular  glands,  pleuritic 
effusion,  and  tubercular  or  rheumatic  joint  disease.  Its  action  here 
consists  simply  of  a  mild  lasting  irritation  of  the  skin,  which  induces 
some  congestion  in  the  subcutaneous  tissues  and  may  thus  aid  in  the 
absorption  of  exudates  in  them  and  may  also  influence  the  deeper 
lying  tissues  and  organs  in  the  same  way  as  other  irritants  (see  page 
72).  There  is,  however,  nothing  specific  in  its  action,  and  it  differs 
from  the  other  skin  irritants  only  in  being  milder  in  action  and  more 
enduring  in  its  effects.  It  seems  unlikely  that  the  small  quantity 
absorbed  can  have  any  appreciable  action.  Some  benefit  often  follows 
from  this  use  of  iodine  in  chronic  inflammations,  but  there  is  no  ques- 
tion that  it  is  very  often  applied  where  more  active  surgical  measures 
are  really  required. 

Iodine  was  formerly  injected  into  cysts  in  order  to  induce  inflamma- 
tion and  adhesion  of  their  walls,  and  thus  to  obliterate  the  cavity. 
It  has  recently  been  used  extensively  to  disinfect  the  skin  before 
operation  (see  page  149). 

Bibliography. 

See  Iodides,  Thyroid  Extract. 

Liebrechl.     Centralbl.  f.  Physiol.,  1897,  p.  835. 

Hofweisler.     Ztschr.  f.  phys.  Chem.,  xxiv,  p.  159. 

Winternitz.     Ibid.,  xxiv,  p.  425. 

Levene.     Amor.  Jour,  of  Phys.,  ii,  p.  15. 

XLI.     THYROID  GLAND. 

The  treatment  of  certain  diseases  by  the  administration  of  thyroid 
gland  and  its  extracts  is  one  of  the  most  satisfactory  examples  of 
rational  therapeutic  progress,  and  the  steps  which  led  to  its  adoption 
may  therefore  be  briefly  mentioned.  In  1882-3,  Kocher  and  Reverdin 
published  observations  made  on  ])atients  whpse  thyroids  had  been 
totally  extirpated,  and  who  had  subsequently  presented  a  series  of 
symptoms  to  which  these  observers  gave  the  name  of  cachexia  thyreo- 


5L'8  HVHSTANCES  ACTING  AFTER  ABSORPTION 

l)riv;i.  Tliey  pointed  out  that  this  condition  resembled  in  many  of  its 
iVatnres  myxopdema,  a  disease  disco\-ered  by  Gull  some  years  before 
and  associated  with  atrophy  of  the  thyroid  gland.  These  observations 
were  confirmed  by  a  number  of  authors,  who  removed  the  thyroids 
from  animals,  and  found  a  cachexia  appear  in  them.  The  next  advance 
was  the  discovery  that  these  symptoms  in  animals  could  be  removed, 
or  at  any  rate  ameliorated,  by  grafting  pieces  of  thyroid  in  the  peri- 
toneal cavity  or  subcutaneous  tissue.  Horsley  suggested  that  myx- 
frdema  should  be  treated  in  the  same  way,  and  Murray  soon  afterward 
introduced  the  treatment  of  this  disease  by  the  su})cutaneous  injection 
of  thyroid  juice.  Even  in  his  first  case,  the  results  were  eminently 
satisfactory,  but  it  w^as  soon  found  that  the  same  results  could  be 
obtained  by  administration  by  the  stomach,  and  a  large  number  of 
cases  have  now  been  recorded  in  which  very  favorable  results,  or  even 
the  complete  disappearance  of  the  symptoms  has  followed  this  medica- 
tion. These  include  not  only  myxoedematous  patients,  but  also  cases 
in  which  the  thyroid  w-as  removed  by  surgical  operation,  or  where  its 
disease  gave  rise  to  symptoms.  That  the  favorable  results  are  due 
to  the  treatment  is  pro^•ed  conclusively  by  the  return  of  the  symptoms 
when  it  is  abandoned. 

The  effect  of  the  thyroid  extract  could  be  explained  only  by  the 
presence  of  some  chemical  principle,  for  the  preparation  of  course 
contained  no  living  cells.  In  the  last  few  years,  this  principle  has  been 
found  in  the  colloid  contents  of  the  gland  follicles  in  the  form  of  a 
globulin,  thyreoglobulin,  which  may  be  extracted  from  the  colloid 
and  gives  the  ordinary  protein  reactions,  but  is  characterized  by  con- 
taining a  small  percentage  of  iodine;  Baumann's  detection  of  this 
clement  in  the  thyroid  gland  was  the  first  intimation  that  it  existed 
in  the  tissues  of  the  higher  animals  and  man.  Thyreoglobulin  is  not 
completely  saturated  Avith  iodine,  for  it  forms  a  higher  combination 
with  it  in  the  test-tube,  but  then  loses  its  specific  action  on  the  animal 
organism.  When  it  is  subjected  to  acids  or  to  artificial  digestion  it 
undergoes  hydrolysis  like  other  proteins,  and  much  of  the  iodine  is 
freed  from  the  organic  combination  in  which  it  exists  in  thyreoglubulin ; 
the  products  of  the  complete  digestion  of  thyreoglobulin  apj^ear  to 
have  no  such  specific  action  as  the  original  })rotein.i  Hunt  states 
that  the  iodine  compound  is  not  the  only  active  principle  in  the  gland, 
for  thyroids  containing  no  iodine  have  a  certain  degree  of  activity, 
though  tills  is  greatly  inferior  to  that  of  glands  containing  iodine.  He 
suggests  that  the  thyreoglobulin  is  therapeutically  active  even  when  it 
contains  no  iodine,  but  that  when  it  is  combined  with  iodine  it  is  much 
increased  in  power.  In  fact  the  amount  of  iodine  in  the  gland  may 
be  estimated  fairly  accurately  from  the  changes  induced  by  its  adminis- 
tration.   At  i)resent  the  efheiency  of  the  preparations  of  the  glands  can 

'  Raumann  bdicvid  that  the  active  principle  was  Thyroiodin,  or  lodoihyrin,  which  he 
obtaimd  by  the  <liK<slioii  of  the  glaii<i;  but  this  is  not  a  definite  substance,  but  a  mix- 
ture of  peptides  combined  with  icjdine,  and  does  not  possess  the  whole  specific  action  of 
the  gland  extracts. 


THYROID  GLAND  529 

only  be  measured  by  the  ainouiit  of  iodine  present,  and  this  \aries  a 
good  deal  in  different  animals  and  in  different  individuals  of  the  same 
species.  For  example,  less  is  found  in  the  glands  of  children  than  in 
adults,  and  after  middle  age  it  lessens  again.  Meat  diet  diminishes  the 
amount  of  iodine,  either  because  it  makes  greater  demands  on  the 
supply,  or  because  too  little  iodine  is  ingested  in  the  food.  Vegetable 
foods,  especially  those  containing  much  iodine,  such  as  beetroot  and 
the  marine  algse,  increase  the  iodine  of  the  thyroid  gland.  Iodine 
given  medicinally  also  augments  it,  and  not  only  iodine  itself,  but 
various  combinations,  such  as  iodoform  and  iodides. 

Thyreoglobulin  treatment  has  the  same  beneficial  effects  as  the 
extract  both  in  myxoedema  and  goitre  in  man  and  in  excision  of  the 
thyroid  in  animals.  This  has  been  disputed  until  recently,  owing  to 
the  fact  that  in  many  cases  the  parathyroid  glands  have  been  removed 
along  with  the  thyroid  in  animal  experiments.  Now  the  removal  of 
the  parathyroids  in  dogs  (on  which  the  experiments  have  generally 
been  performed)  leads  to  a  series  of  symptoms  arising  from  the  central 
nervous  system,  and  these  are  not  affected  by  thyroid  medication. 
When  the  thyroid  alone  is  removed,  the  symptoms  are  relieved  by 
either  thyreoglobulin  or  thyroid  extract,  and  the  former  therefore 
represents  the  whole  therapeutic  virtues  of  thyroid  extract,  although 
it  is  possible  that  the  gland  may  have  other  functions  than  secretion. 
Thyroid  preparations  are  thus  used  to  replace  the  secretion  of  the 
thyroid  gland,  when  it  is  deficient  from  any  cause. 

Action.^ — The  thyroid  extracts  and  thyreoglobulin  seem  to  be  devoid 
of  effect  in  many  normal  animals  and  patients,  unless  when  given  in 
enormous  quantities.  In  others  they  cause  some  unpleasant  symptoms, 
which  occur  more  especially  in  myxoedema  and  goitre.  These  symptoms 
are  partly  subjective  and  indefinite,  such  as  headache,  wandering 
pains,  or  general  weakness,  while  others  are  evidently  due  to  circulatory 
changes,  and  consist  of  a  feeling  of  fullness  and  congestion  of  the  head, 
palpitation  of  the  heart,  and  acceleration,  sometimes  weakness,  of  the 
pulse.  Tremors  in  the  arms  and  legs  point  to  changes  in  the  central 
nervous  system,  while  loss  of  appetite  and  diarrhoea  indicate  that  the 
alimentary  canal  is  not  exempt  from  its  influence.  Perspiration  is 
often  complained  of,  especially  in  myxoedema,  and  a  rise  of  temperature 
also  occurs  not  infrequently.  The  most  striking  effect  in  the  majority 
of  cases  is  a  rapid  loss  of  weight. 

In  normal  animals  thyroid  extract  injected  intravenously  in  large 
quantities  is  said  to  accelerate  the  heart  and  lower  the  blood-pressure 
sometimes,  and  even  when  given  by  the  mouth  repeatedly  for  several 
days,  it  may  cause  some  acceleration.  This  acceleration  of  the  heart  has 
been  attributed  by  some  investigators  to  stimulation  of  the  accelerator 
centre,  by  others  to  direct  action  on  the  heart;  it  does  not  seem  to  be 
due  to  any  changes  in  the  inhibitory  apparatus  and  is  not  by  any  means 
an  invariable  result  of  thyroid  treatment.  In  some  instances  in  which 
it  is  induced  in  animals  by  prolonged  treatment  with  large  doses,  it 
may  arise  from  the  metabolic  changes  or  from  the  effects  on  the  intestine, 
34 


530  SUBSTANCES  ACTING  AFTER  ABSORPTION 

Loss  of  Hesh  aiul  thirst  liave  been  observed,  even  when  the  appetite 
is  f]coo(l  atid  sufficient  food  and  water  are  siippHed.  The  urine  is 
uniformly  increased  in  amount.  A  number  of  observers  ha\e  found 
that  the  continued  administration  to  animals  of  thyroid  preparations 
in  large  amounts  leads  to  diarrhoea,  muscular  Meakness,  especially  in 
the  hind  extremities,  emaciation,  gastro-enteritis,  nephritis,  and  fatty 
degeneration  of  various  organs.  In  other  instances  no  such  symptoms 
ha\e  been  elicited,  the  animals  remaining  perfectly  normal  after  pro- 
longed treatment.  Different  species  of  animals  vary  greatly  in  their 
susceptibility  to  thyroid  treatment,  and  this  may  explain  some  of  the 
anomalous  results  recorded.  In  other  instances,  the  absence  of  symp- 
toms may  have  been  due  to  the  extract  having  been  prepared  from 
thyroids  containing  little  iodine. 

As  may  be  gathered  from  the  above,  great  discrepancies  occur  in 
the  accounts  of  the  effects  of  thyroid  on  normal  animals.  The  fall 
in  weight  seems  to  be  the  most  common  result. 

The  effects  of  thyroid  extract  on  the  Metabolism  \\a\Q  been  repeatedly 
examined,  with  very  uniform  results.  One  of  the  most  striking  features 
in  many  individuals  is  the  rapid  loss  of  weight,  which  often  amounts 
to  several  pounds  per  week.  Another  is  the  increase  in  the  amount  of 
nitrogen  in  the  urine,  which  occurs  both  in  goitre  and  myxoedema, 
and  very  often  in  apparently  normal  persons.  More  nitrogen  is  excreted 
in  the  urine  frequently  than  is  taken  in  the  food,  that  is  to  say,  the 
treatment  leads  to  the  destruction  of  the  proteins  of  the  tissues.  If 
more  nitrogenous  food  be  given,  howe\er,  this  may  be  arrested,  and  in 
fact  if  large  quantities  of  meat  be  taken,  less  nitrogen  may  be  excreted 
than  is  taken  in  the  food,  so  that  although  the  patient  is  losing  in  weight, 
he  may  be  actually  increasing  in  nitrogenous  tissue.  The  increase  in  the 
nitrogenous  excretion  is  not  stayed  by  the  administration  of  carbo- 
hydrates and  fats  on  the  other  hand,  because  the  glycogenic  function 
of  the  liver  is  disorganized  by  thyroid  treatment  (p.  531).  The  increase 
in  the  nitrogen  of  the  urine  is  accounted  for  almost  entirely  by  the 
increase  in  the  urea;  the  ammonia  shows  a  very  slight  rise,  while  the 
uric  acid  and  the  creatinin  remain  almost  unchanged;  some  creatin 
appears  in  the  urine.  The  increased  waste  of  the  proteins  only  accounts 
for  about  one-sixth  of  the  loss  of  w^eight,  the  other  five-sixths  being 
evidently  due  to  the  more  rapid  oxidation  of  fats  and  the  removal  of 
ffuid  from  the  body.  The  more  rapid  oxidation  is  further  e\idenced 
by  the  increased  amount  of  oxygen  absorbed  and  of  carbonic  acid 
exhaled  by  the  lungs  in  cases  of  myxoedema,  and  sometimes  in  obesity 
and  goitre  treated  with  the  extract.  The  removal  of  fluid  from  the 
body,  perhaps  the  most  potent  factor  in  reducing  the  weight  in  these 
cases,  is  shown  by  diuresis,  which  occurs  in  myxcrdema  especially,  but 
also  in  obesity.  This  diuresis  has  been  ascribed  to  some  specific  action 
on  the  kidney,  or  to  the  changes  in  the  circulation,  but  may  perhaps 
be  due  to  the  increased  excretion  of  urea  and  other  urinary  substances. 
That  the  kidney  is  acted  on  in  some  cases  is  shown  by  the  occasional 
ai)i)earanrc'  of  iili)uniin  in  the  urine  of  i);iti('nts  treated  with  thyroid 


THYROID  GLAND  531 

preparations.  The  pli()sj)liates  excreted  are  iiiereased  in  the  same 
ratio  as  the  nitrogen,  and  the  increase  is  obviously  due  to  the  same 
cause,  augmented  protein  waste. 

In  some  cases  sugar  lias  been  found  in  the  urine  after  thyroid  treat- 
ment, and  in  a  considerable  percentage  of  persons  it  seems  to  cause  a 
tendency  to  glycosuria,  as  is  shown  by  the  appearance  of  sugar  in  the 
urine  after  the  ingestion  of  large  quantities  of  sugar,  which  would 
normally  be  oxidized  in  the  tissues.  After  thyroid  feeding  the  liver  is 
found  to  contain  only  traces  of  glycogen  owing  to  an  inhibition  of  the 
glycogenic  function,  and  this  may  contribute  to  the  increased  elimi- 
nation of  nitrogen  in  the  urine  (Cramer  and  Krause). 

The  thyroid  extract  loses  its  therai)eutic  efficacy  if  it  is  completely 
iligested  by  the  pancreatic  juice.  Yet  thyroid  extract  given  by  the 
mouth  is  highly  effective;  this  seems  to  indicate  that  some  of  the 
thyreoglobulin  is  absorbed  from  the  intestine  unchanged,  or  at  any 
rate  without  having  imdergone  complete  hydrolysis. 

After  tliyroid  preparations  have  been  administered,  iodine  is  found 
in  the  urine  in  the  form  of  iodides,  so  that  the  iodine  comi)ound  is 
evidently  decomposed,  at  any  rate  in  part,  in  the  body.  The  rest  of 
the  iodine  is  taken  up  by  the  thyroid  gland. 

Hunt  has  recently  made  the  observation  that  the  administration  of 
thyroid  extract  diminishes  the  susceptibility  of  mice  to  acetonitril 
(CH3CN),  a  poison  which  seems  to  act  by  freeing  prussic  acid  in  the 
tissues,  and  the  degree  of  protection  afforded  varies  directly  with  the 
amount  of  iodine  of  the  gland.  On  the  other  hand,  it  increases  the 
susceptibility  of  rats  to  the  same  poison,  and  morphine  is  more  toxic 
to  both  mice  and  rats  when  they  have  been  treated  with  thyroid  for 
some  time  previously.  The  presence  of  even  very  minute  quantities 
of  thyroid  extract  may  be  demonstrated  by  feeding  these  animals  with 
it  and  testing  their  resistance  to  these  poisons. 

In  regard  to  their  reaction  to  thyroid  medication,  individuals  vary  consid- 
erably, for  many  are  scarcely  affected  by  it  in  any  way,  and  this  is  particu- 
larly true  of  children,  while  others  lose  weight  rapidh',  and  under  larger  doses 
show  symptoms  of  poisoning  (thja-oidism) .  These  seem  to  be  more  easily 
elicited  in  goitre  and  mj^xcedema  than  in  ordinary  cases. 

The  fact  that  "thyroidism"  occurs  more  frequently  in  mj^xoedematous 
than  in  normal  persons  seems  difficult  of  explanation,  and  it  has  been  sug- 
gested that  the  symptoms  are  due,,  not  to  the  extract  itself,  l)ut  to  the  products 
of  its  action.  It  maj'  be  supposed  that  in  myxoidema  a  large  amount  of  some 
substance  accumulates  in  the  tissues,  because  the  secretion  is  not  present  in 
sufficient  quantity  to  decompose  it,  and  that  when  the  thyroid  treatment 
is  commenced,  the  body  is  flooded  with  the  products  of  decomposition  and  these 
give  rise  to  symptoms.  In  normal  persons,  on  the  other  hand,  there  is  no  such 
accumulation,  and  the  extract  therefore  induces  no  symptoms  until  it  is  given 
in  such  quantity  as  to  induce  intoxication  itself.  For  some  years  the  view  has 
prevailed  that  exophthalmic  goitre,  or  Graves'  (Basedow's)  disease,  arises  from 
an  excess  of  the  specific  secretion  of  the  gland  being  poured  into  the  general 
circulation,  and  a  good  deal  of  ingenuity  has  been  employed  in  showing  that  the 
symptoms  of  Graves'  disease  maj-  be  induced  b}'  the  administration  of  thyroid 
extracts.  Unbiassed  examination  indicates,  however,  that  thyroidism  and 
Graves'  disease  are  quite  distinct  conditions,  which  have  few  features  in  common 


532  SUBSTANCES  ACTING  AFTER  ABSORPTION 

and  wliich  ofTcr  many  contrasts.  None  of  the  more  characteristic  symptoins  of 
cxophlhalniic  jroilre  have  been  observed  in  man  or  animals  from  the  administra- 
tion of  thvroid  jireparations. 

Io(hne,  as  lias  been  stated,  increases  the  iodine  of  the  j^land,  and  this  exi)huns 
tlie  beneficial  effects  formerly  seen  in  goitre  from  the  application  of  iodine 
internally  and  locally.  When  iodine  was  efficient  in  those  cases,  and  any  con- 
sideral)lc  diminution  of  the  gland  occurred,  it  was  often  accompanied  by  symp- 
toms exactly  resembling  those  produced  by  large  doses  of  the  extract.  Those 
symi)toms  were  caused  by  small  quantities  in  some  patients,  while  much  larger 
doses  had  no  such  effect  in  others— a  fact  which  gave  rise  to  some  discussion 
and  several  erroneous  theories.  Sometimes  the  acute  symptoms  passed  into  a 
cachexia  of  very  long  standing.  The  quantity  of  iodine  required  to  act  in 
goitre  is  much  greater  than  the  iodine  of  the  thyroid  extract  necessary,  and  this 
shows  that  the  latter  acts  not  merely  as  an  iodine  compound,  but  as  the  specific 
substance  of  the  gland.  If  the  thyroid  gland  tissue  is  intact  a_nd  capable  of 
functioning,  iodine  or  iodides  are  useful  in  these  cases  of  thyroid  inefficiency 
because  they  lead  to  the  formation  of  thyreoglobulin.  But  when  the  secretory 
cells  of  the  "gland  are  entirely  destroyed,  iodine  cannot  give  relief  because  no 
thyreoglobuhn  can  be  formed;  here  the  specific  secretion— thyreoglobulin— 
itself  must  be  supplied.  Various  iodine  compounds,  such  as  iodalbumin  and 
iodospongin  (the  iodine  compound  of  the  sponge)  have  been  shown  to  be  prac- 
tically inert  in  goitre. 

Preparatioxs. 

Thyroideu.m  SiccuM  (B.  p.),  Glandul.e  Thyroide.e  Sicc.e  (U.  S.  P.), 
a  powder  prepared  from  the  fresh  and  healthy  thyroid  gland  of  the  sheep.  It 
forms  a  light,  dull-brown  powder  with  a  faint,  meat-like  odor  and  taste,  free 
from  any  odor  of  putrescence.  About  16  grs.  represent  an  entire  gland.  Dose, 
0.25  G.  (4  grs.);  B.  P.,  3-10  grs. 

Thyroid  medication  may  be  carried  out  in  a  number  of  difTerent  ways. 
The  old  method  of  ordering  the  raw  or  toasted  gland  to  be  taken  daily  may 
now  be  said  to  be  rendered  obsolete  by  more  elegant  preparations,  such  as 
dried  thyroid  or  thyroid  extract  in  powder  form  or  in  pills  or  tablets.  These 
ought  not  to  be  prescribed  in  large  quantities,  as  they  are  liable  to  undergo 
putrefaction  unless  when  carefully  kept;  satisfactory  results  can  be  expected 
only  when  the  preparation  has  been  assayed  for  iodine.  The  dose  should  be 
smiiU  at  first  (c.  g.,  \  gr.  of  the  dried  gland  every  evening  for  the  first  week  of 
treatment),  and  should  be  gradually  increased,  until  improvement  sets  in  or 
unpleasant  symptoms  arise. 

Therapeutic  Uses. — Thyroid  extract  is  not  a  dangerous  remedy, 
unless  in  certain  cases.  In  myxcedema,  however,  it  should  be  used 
with  care,  especially  if  the  heart  is  seriously  affected,  as  the  cardiac 
nniscle  may  be  unable  to  meet  the  requirements  of  the  accelerated 
rhythm;  several  serious  cases  and  one  or  two  fatalities  ha^■e  already 
been  recorded  in  these  conditions. 

Thyroid  extract  is  useful  as  a  substitute  for  the  normal  gland  secre- 
tion in  cases  where  the  latter  is  wanting  or  deficient;  thus  in  atro])hy 
of  the  thyroid  in  adults  (myxoedema),  after  its  extirpation  (cachexia 
thyreopriva),  and  in  its  congenital  absence  or  atrojihy  (s])oradic  cretin- 
ism) the  most  remarkable  iuii)rovement  follows  its  use,  the  jiatients 
from  a  condition  of  idiocy  regaining  practically  normal  intelligence. 
It  is  of  the  first  imi)ortaiice  to  connnence  the  treatment  as  soon  as  the 
condition  is  recognized  and  to  continue  it  with  careful  observation 
throughout  life,  for  its  abandonment  leads  to  a  s])cedy  ri-lapsc  to  the 


THYROID  GLAND 


53 


former  condition.  At  the  same  time  the  dose  should  not  be  larger  than 
is  necessary  and  may  have  to  be  \aried  from  time  to  time  as  circum- 
stances change.  Unless  the  treatment  is  begun  early  no  complete 
return  to  the  normal  is  obtained,  although  improvement  is  observed 
even  in  neglected  cases. 

The  use  of  thyroid  preparations  in  these  conditions,  in  which  the 
gland  is  atrophied,  is  readily  understood.  On  the  other  hand  it  seems 
anomalous  to  employ  it  in  cases  of  enlargement  of  the  gland  (goitre). 
Yet  great  improvement  is  seen  from  thyroid  treatment  in  many  of 


Fig.  67 


Fic.  OS 


A  case  of  sporadic  cretinism.  Fig.  67,  before  treatment,  age  twenty-three  months, 
height  28  inches,  circumference  of  the  abdomen  19  inches.  Fig.  68,  after  treatment  with 
thyroid  extract  for  5^  months,  height  30  inches,   circumference  of  abdomen   15  inches. 

(Osier.) 

these  cases.  In  goitre  the  gland  is  enlarged  (hyperplasia),  but  this 
does  not  indicate  an  excessive  formation  of  secretion,  but  the  reverse; 
the  gland  hypertrophies  in  an  effort  to  compensate  for  the  poverty  of 
its  secretion  in  thyreoglobulin  and  iodine,  and  when  the  condition  is 
treated  with  thyroid  extract  the  hyperplasia  lessens  and  the  gland 
assumes  its  normal  condition  as  far  as  the  secretory  epithelium  is 
concerned,  though  it  may  be  enlarged  through  the  presence  of  large 
colloid  masses.  The  treatment  of  goitre  with  thyroid  extract  is  thus 
of  the  same  nature  as  the  treatment  of  thyroid  atrophy,  for  though 


534  SUBSTANCES  ACTING  AFTER  ABSORPTION 

the  ijlaiul  is  enlarged  it  is  unal)Ie  to  fulfill  its  function.  Goitre  does  not 
require  the  ])ernianent  use  of  thyroid  as  a  general  rule;  the  treatment 
is  carried  on  only  until  the  gland  is  reduced  in  size. 

The  decrease  in  weight  occurring  in  thyroid  medication  suggested  its 
use  in  obesitA',  and  it  has  been  followed  by  some  loss  of  weight  in  a 
certain  number  of  cases,  es])ecially  when  accompanied  by  proper  dietetic 
treatment.  In  many  instances  it  has  had  little  or  no  efi'ect,  however,  and 
the  initial  encouraging  action  is  seldom  maintained  when  the  treatment 
is  continued,  the  daily  loss  of  weight  gradually  becoming  smaller  until 
it  ceases  altogether.  The  amount  of  fat  actually  destroyed  seems  to  be 
trifling,  Magnus-Levy  esthnating  that  about  one  ])oun(l  disappears 
in  ten  days,  which  is  much  less  than  can  be  got  rid  of  by  judicious 
exercise  and  an  appropriate  dietary.  Besides,  the  continued  use  of 
thyroid  in  these  cases  is  not  altogether  devoid  of  danger.  Several 
authorities  state  that  in  some  cases  the  dietetic  treatment  fails  unless 
it  is  accompanied  at  first  by  thyroid  medication;  they  therefore  give  a 
few  doses  of  thyroid  to  initiate  the  treatment  and  continue  it  by  dietetic 
measures.  ]\Iany  of  the  ant  if  at  remedies  put  on  the  market  contain 
tliNToid  extract  and  their  continued  use  has  led  to  serious  sj'mptoms 
ill  a  number  of  cases. 

In  some  skin  diseases,  especially  in  psoriasis,  it  has  been  of  benefit,  though 
not  by  any  means  invariably,  and  in  syphilis  of  okl  standing  some  improvement 
has  been  seen.  This  is  probably  due  to  the  iodine  contained,  and  not  to  the 
specific  gland  secretion.  At  the  same  time  the  peculiar  combination  in  which  the 
iodine  is  present  may  perhaps  be  more  easily  made  use  of  by  the  economy  than 
the  ordinary  inorganic  preparations. 

The  im])rovement  seen  in  the  brain  symptoms  in  myxoe(knna  and  cretinism 
suggested  its  use  in  other  mental  diseases,  but  the  action  in  the  former  is  due 
to  its  substitution  for  the  normal  secretion,  and  little  or  no  effect  has  followed 
in  oi'dinary  cases  of  mental  disease. 

bi  (Jraves'  disease,  thyroid  treatment  is  generally  injurious,  or  at  least  leads 
to  no  improvement.  But  in  some  cases  very  small  doses  have  proved  valuable, 
prol)ably  because  in  those  cases  the  hyperplasia  of  the  gland  was  ])assing  into 
atrophy. 

Bibliography. 

Baumrinn  u.  Roos.     Ztschr.  f.  physiologischc  Chemie,  xxi,  xxii. 

Roos.     Ibid.,  xxi,  xxii,  xxv,  pp.  1  and  242;    xxviii,  p.  40. 

Baumann  u.  Goldmajin.     Miinch.  med.  Woch.,  1896,  p.  1153. 

Ewald.     Die  Erkraukungen  dor  Schilddriise — Myxcdem  uiid  Cretinismus. 

Miihius.  Dio  Basodowschc  Kraiikhoit,  Wien,  1896.  These  two  arc  contained  in 
Nothnagf^l's  Sijociclle  Pathologic  iind  Thcrapie,  Bd.  xxii. 

Ilutchimon.  Brit.  Med.  .lourn.,  1896,  i.  p.  722;  1897,  i.  p.  19-1.  .lotirn.  of  Pliys., 
XX,  p.  474;    xxiii,  p.  178. 

Oswald.  Zts.  f.  phys.  Chem.,  xxiii,  p.  265;  xxvii,  p.  14;  xxxii,  p.  121;  Virchow's 
Arch.,  dxix,  p.  444.    Arch.  f.  cxp.  Path.,  Ix,  p.  115;   Ixiii,  p.  203. 

Scluindorff.     Pfliiger's  Arch.,  Ixiii,  p.  423;    Ixvii,  p.  395. 

Benscn.     Virchow's  Arch.,  clxx,  p.  229. 

Ridd  Hunt.  Hygienic  Laboratory  Bulletin,  No.  17,  Washington,  1909.  .lonrn.  of 
IMi.-irniaeology,  ii,  p.  15. 

Siruuse  (ind  Vocutlin.     .Joiirn.  of  I'liarniacology  and  \'.\\i.  Therap.,  i,  p.  123. 

/Hum.     Pfliiger's  Arch.,  Ixxvii,  \>.  70. 

Volt.      Zlsehr.  f.  Biol.,  XXXV,  p.  11(1. 

Cunniiioliuiii.     .lonrn.  rif  I^xp.  Med.,  iii,  p.  I  17. 


SULPHITES  535 

Magnus-Levy.     Ztschr.  f.  klin.  Med.,  xxxiii,  p.  2G9. 

Hcllin.     Arch.  f.  exp.  Path.  u.  Pharm.,  xl,  p.  121. 

Howell,  ChiUenden,  Adami,  Putnam,  Kinnicutt,  and  Osier.  Transactions  of  the  Con- 
gress of  American  Physicians  and  Surgeons,  iv,  pp.  70-206. 

Anderson  u.  Bergmann.     Skand.  Arch.  f.  Physiol.,  viii,  p.  326;    xiv,  p.  220. 

Georgiewski.     Ztschr.  f.  klin.  Med.,  xxxiii,  p.  153. 

Edmunds.     Proc.  Roy.  Soc,  Ixv,  p.  368. 

Murray.     Practitioner,  April,  1901. 

Pick  u.  Pineles.     Zeitschr.  f.  exp.  Path.  u.  Ther.,  vii,  p.  518. 

Marine  and  Lenhart.  Arch,  of  Intern.  Med.,  iv,  p.  440;  vii,  p.  506;  viii,  p.  265. 
.lourn.  Exp.  Med.,  xii,  p.  311;   xiii,  p.  455. 

Osier  and  Flack.     Ztschr.  f.  Biol.,  Iv,  p.  83. 

Carlson,  Rooks,  and  McKie.     Amer.  Journ.  Physiol.,  xxx,  p.  129. 

Cramer  and  Krause.     Proc.  Roy.  Soc,  B,  Ixxxvi,  p.  550. 


XLH.  ,  SULPHITES. 

The  sulphites,  an  unimportant  group  of  bodies  from  a  therapeutic  point 
of  view,  are  rapidly  oxidized  to  sulphates  in  contact  with  Uving  matter. 

Injected  into  frogs,  sulphite  of  sodium  causes  great  muscular  weakness  and 
depression,  and  eventually  paralysis  of  the  central  nervous  system,  beginning 
in  the  brain  and  descending  to  the  spinal  cord.  Later,  the  heart  becomes  weak 
and  ceases  in  diastole,  and  the  peripheral  nerve  terminations  and  the  muscles  are 
paralyzed.  In  the  dog  and  cat  subcutaneous  injection  causes  nausea,  vomiting, 
restlessness  and  dyspnoea,  and  great  muscular  weakness,  ending  in  arrest  of  the 
respiration,  and  a  little  later  of  the  heart.  In  the  rabbit  the  symptoms  consist 
of  dyspnoea  and  muscular  weakness  without  loss  of  spontaneous  movement.  _ 
Intravenous  injection  shows  that  the  chief  seat  of  action  of  the  sulphites  is 
the  medulla  oblongata,  in  which  they  depress  the  respiratory  and  vasomotor 
centres.  The  heart  is  acted  on  directly  apparently,  for  the  pulse  is  slow,  and. 
the  muscular  walls  of  the  vessels  are  also  weakened. 

If  large  quantities  be  absorbed  rapidly,  they  prove  immediately  fatal,  but 
if  the  respiration  be  kept  up  for  a  short  time,  recovery  may  follow,  because 
the  poisonous  sulpliite  is  changed  to  the  harmless  sulphate  and  excreted. 
Almost  all  of  the  sulphite  absorbed  into  the  blood  is  oxidized  to  the  sulphate, 
a  mere  trace  being  excreted  in  the  urine  unchanged.  The  thiosulphate  is 
apparently  oxidized  with  greater  difficulty,  for  Walko  found  30-50  per  cent, 
eliminated  by  the  kidneys  unaltered. 

Much  larger  quantities  are  required  to  poison  animals  when  given  by  the 
mouth  than  when  injected  subcutaneously,  because  the  salt  is  changed  to  the 
harmless  sulphate  before  it  reaches  the  blood.  Some  irritation  of  the  stomach 
is  caused  from  the  sulphurous  acid  being  freed  by  the  gastric  juice,  and  this 
inducess  vomiting  in  the  dog. 

Large  doses  of  sulphites  have  been  taken  by  man  without  symptoms  of 
poisoning  being  induced.  Even  30-40  gms.  are  said  to  have  been  swallowed, 
but  in  most  preparations  of  sulphite  a  large  proportion  of  sulphate  is  present, 
and  it  is  impossible  to  state  how  much  sulphite  was  really  contained  in  these 
doses.  Symptoms  of  gastric  and  intestinal  irritation  have  been  induced  by 
comparatively  small  quantities. 

Sodii  Sulphis  (U.  S.  P.,  B.  P.)  (NaaSOa+THaO),  a  soluble  salt  which  oxidizes 
to  the  sulphate  in  the  air,  is  feebly  alkaline  and  has  a  cool,  saline  taste.  1  G. 
(15  grs.);  B  P.,  5-20  grs. 

Sodii  Thiosulphas  (U.  S.  P.)  (Na2S203+5H20)  is  very  soluble,  has  a  cool, 
saline  taste  and  is  neutral  in  reaction.    1  G.  (15  grs.). 

Solutions  of  these  salts  have  been  used  to  a  limited  extent  as  antiseptic 
mouth- washes  in  aphthae,  and  have  been  prescribed  in  some  forms  of  fermen- 
tation in  the  stomach.  They  were  formerly  reputed  to  be  of  benefit  in  cases 
of  pysemia  from  their  supposed  action  as  antiseptics  in  the  blood,  )jut  have 
never  proven  to  be  of  any  real  value. 


'^?,{\  SUBSTANCES  ACTING  AFTER  ABSORPTION 


BiBLIOCRAl'IlY. 

PJeiffcT.     Arch.  f.  cxp.  Path.  u.  Pharm.,  xxvii,  p.  261. 

Kionka.     Ztschr.  f.  Hygionc!,  xxii,  p.  351;  xli,  p.  12.3. 

Walko.     Arch,  de  Pharmakodynam.,  iv,  p.  311. 

Lange.     Arch.  f.  Hj'giene,  xl,  p.  143. 

Rost  u.  Franz.     Arb   a.  d.  k.  Gesundheitsamte,  xxi,  p.  312;  xliii,  p.  187. 

AltschiUer.     Arch.  f.  Hj^giene,  xlviii,  p.  114. 

XLHI.    HYDRATES  AND  CARBONATES  OF  THE  ALKALIES. 

Tlie  hydrates  and  carbonates  of  potassium,  sodium  and  lithium 
owe  their  pharmacological  action  entirely  to  the  non-metallic  ion, 
which  is  so  much  more  powerful  than  the  metal  that  the  latter  may 
be  discounted.  In  the  hydrates  the  active  constituent,  then,  is  — IIO. 
The  carbonates  and  bicarbonates  dissociate  into  K-  or  Na-ions  and 
— CO3,  but  the  latter  rapidly  combines  with  the  hydrogen  of  the  water 
and  thus  frees— OH,  so  that  the  final  effect  is  the  same  as  if  a  hydrate 
had  been  administered,  except  that  the  carbonates  are  less  rapidly 
dissociated  than  the  hydrates,  and,  less  —OH  being  formed,  are  less 
violent  in  their  action.  This  hydroxyl  ion,  then,  is  what  induces  the 
alkaline  reaction  of  the  solutions  and  their  pharmacological  effect, 
the  metallic  ion  only  serving  as  a  means  of  applying  the  hydroxyl  ion, 
but  not  affecting  the  pharmacological  action.  In  other  words  the 
alkalinity  (hydroxyl  ion)  of  the  hydrates  and  carbonates  determines 
their  action;  the  metal  has  no  practical  importance. 

It  is  therefore  erroneous  to  take  the  hydrates  and  carbonates  as  tjiMfyiiig 
the  action  of  potassium  or  sodium,  for  in  these  the  metallic  action  is  much  less 
distinct  than  in  the  chlorides,  the  Cl-ion  being  practically  inert,  while  the 
hydroxyl  is  exceedingly  poisonous. 

"  It  may  be  remarked  in  passing  that  the  importance  of  the  reaction  between 
alkalies  and  acids  lies  not  in  the  combination  of  the  metal  with  the  anion  of  the 
acid,  but  in  the  combination  of  the  powerful  liydroxyl  ion  with  the  hydrogen 
ion  of  the  acid.  In  the  effects  of  potassic  hydrate  in  the  stomach,  the  mam 
importance  is  to  be  attached  not  to  the  potassic  chloride  formed,  but  to  the 
water  (K— HO+H— C1  =  K— CI+H2O),  for  the  potassium  and  chloride  ions 
remain  unchanged  by  the  operation,  while  the  hydroxyl  and  the  hydrogen  ions 
disappear. 

Action.— The  pharmacological  action  of  this  group  is  due  to  their 
l)()wers  of  neutralizing  acids  and  of  dissolving  proteins  and  changing 
them  to  alkali-proteins,  and  in  a  less  degree  to  their  saponifying  fat. 
They  have  in  addition  the  ordinary  salt-action,  and  in  concentrated 
solutions  withdraw  fluid  from  the  tissues. 

The  solution  of  proteins  by  the  alkalies  and  the  characters  of  tlu> 
compounds  thus  formed  outside  the  body  are  well  known  and  need 
not  be  entered  into  here.  The  same  solvent  action  is  observed  in  the 
living  tissues  whenever  the  hydrates  and  carboniitcs  come  in  contact 
with  thcni  in  siiflicient  concentration.  The  hydrates  are,  of  course, 
much  more  i)()\v(rfiil  solvents  than  the  carbonates,  and  these  than  the 
bjcarbonatrs.     hi  \crv  dihitc  solutions  this  solvent  action  is  exercised 


HYDRATES  AND  CARBONATES  OF  THE  ALKALIES  537 

only  on  the  superficial  tissues,  but  when  stronger  solutions  are  used, 
or  when  even  weak  solutions  remain  long  in  contact  with  the  tissues, 
they  tend  to  penetrate  more  dee])ly  and  cause  widespread  destruction 
or  corrosion.  These  bodies  form  soluble  compounds  with  the  proteins 
and  are  only  slowly  neutralized  by  the  tissues,  so  that  no  such  barrier 
is  raised  against  their  penetration  as  is  met  by  some  other  corrosives. 

Applied  to  the  Skin  weak  solutions  dissolve  the  superficial  layer  of 
horn\'  matter  and  the  oily  secretions  of  the  glands,  and  thus  cleanse 
the  surface  more  thoroughly  than  water  or  solutions  of  neutral  salts. 
When  applied  for  some  time,  they  penetrate  more  deeply  and  cause 
some  slight  irritation  and  redness.  Concentrated  solutions  dissolve 
the  skin  and  cause  necrosis  of  the  deeper  tissues,  generally  covered 
by  a  semitransparent  crust  Avhich  falls  off  in  the  course  of  a  few  days, 
leaving  an  ulcer.  The  solutions  of  the  carbonates  are  much  less 
corrosive  than  those  of  the  hydrates,  and  induce  actual  lesion  of  the 
skin  only  under  exceptional  circumstances,  such  as  very  prolonged 
application. 

In  the  Mouth  the  hydrates  and  carbonates  have  a  characteristic 
"alkahne"  taste,  and  dissolve  the  superficial  layers  of  the  lining 
membrane  and  the  mucus  of  the  secretions.  The  lips,  tongue,  and 
gums  assume  a  bright  red  color  from  the  irritation  and  feel  soapy  to 
the  touch.  Concentrated  solutions  may  cause  deep  corrosion,  as  in 
the  skin,  while  very  weak  solutions  have  no  effect  except  the  char- 
acteristic taste  and  a  reflex  flow  of  saliva.  The  corrosion  caused  by 
strong  solutions  extends  to  the  throat  and  oesophagus,  and  may  either 
prove  immediately  fatal  or  may  give  rise  to  cicatrices  subsequently. 

The  eftect  of  the  hydrates  and  carbonates  in  the  Stomach  has  been 
much  disputed,  and  even  now  it  is  impossible  to  explain  some  of  the 
therapeutic  results.  Small  quantities  are  undoubtedly  neutralized  by 
the  hydrochloric  acid  of  the  gastric  juice  and  act  no  longer  from  their 
alkalinity,  but  merely  from  their  effects  as  salts,  if  at  all.  Larger 
quantities  render  the  contents  of  the  stomach  neutral  or  alkaline  and 
thus  prevent  gastric  digestion.  Very  concentrated  solutions  corrode 
the  walls  of  the  stomach  and  may  prove  immediately  fatal  from  caus- 
ing perforation  into  the  peritoneal  cavity,  while  if  the  corrosion  is  not 
so  severe,  and  the  patient  recovers  from  the  shock  and  collapse,  gastric 
ulcer  and  cicatrices  may  result. 

It  is  very  frequently  stated  that  alkalies  and  alkaline  carbonates 
induce  a  more  rapid  secretion  of  the  gastric  juice.  In  fact,  some 
writers  go  so  far  as  to  assert  that  it  is  impossible  to  render  the  con- 
tents of  the  stomach  alkaline  except  bj'  the  use  of  poisonous  doses, 
because  the  gastric  juice  is  so  rapidly  augmented  by  the  alkalies. 
This  belief  seems  to  be  founded  on  the  old  aphorism  contraria  coiitra- 
riis  stiinulantur,  which  proves  to  have  no  greater  basis  in  fact  than 
other  similar  dogmas.  It  has  been  demonstrated  experimentally  in 
dogs  that  alkaline  carbonates,  whether  given  by  the  mouth  or  injected 
into  the  stomach  through  a  gastric  fistula,  do  not  influence  the  gastric 
secretion,  and  Reichmann  has  recently  shown  that  in  man  distilled 


oils  ,WDSTANCES  ACTING  AFTER  ABSORPTION 

watcT  iiitToases  tlie  free  acid  and  the  chlorides  of  the  stomach  con- 
tents as  mucli  as^an  equal  amount  of  an  alkaline  solution.  The  only 
satisfactory  examinations  of  the  question,  therefore,  show  that  the 
alkalies  have  no  effect  whatsoever  on  the  activity  of  the  secretory 
•ilands  of  the  stomach.  On  the  other  hand,  they  may  affect  the  juice 
already  secreted  by  making  it  neutral  or  even  alkaline,  and  may  thus 
render  it  entirely  useless  for  digestion  and  disinfection.  Of  course 
in  hyperacidity  of  the  stomach,  the  alkalies  may  be  of  benefit  by 
lessening  the  amount  of  free  acid  present. 

Dilute  solutions  of  the  alkalies  may  act  as  slight  irritants  to  the 
stomach  wall  and  thus  improve  its  circulation,  and  lessen  pain,  eruc- 
tation and  distention,  very  much  in  the  same  way  as  other  slight  gas- 
tric irritants,  such  as  the  volatile  oils.  In  the  case  of  the  carbonates 
and  bicarbonates,  this  carminative  action  may  be  strengthened  by  the 
carbonic  acid  lil)erated  by  the  hydrochloric  acid.  In  addition,  they 
tend  to  render  the  mucus  less  tenacious,  or  may  dissolve  it  completely, 
and  thus  improve  the  condition  of  the  stomach.  Their  effects  on  the 
movements  of  the  stomach  require  further  investigation.  The  pylorus 
oi)ens  normally  for  the  escape  of  the  gastric  contents  only  when  the 
reaction  is  distinctly  acid,  and  it  would  therefore  be  expected  that  alkali 
would  delay  the  discharge  into  the  duodenum;  but  on  the  other  hand 
neutral  fluids  pass  rapidly  through  the  stomach.  It  is  therefore  possible 
that  alkali  may  delay  the  evacuation  of  the  stomach  when  given  with 
solid  food,  but  may  have  less  effect  when  taken  with  abundant  water. 
The  arrival  of  acid  in  the  duodenum  normally  causes  constriction 
of  the  pyloric  orifice,  and  this  may  perhaps  be  lessened  when  alkalies 
are  given,  particularly  in  cases  of  hyperacidity;  but  the  action  of 
alkali  on  this  reflex  is  still  undetermined. 

In  the  small  Intestine  the  alkalies  have  been  shown  to  have  an  in- 
direct effect,  through  their  diminishing  the  acidity  of  the  gastric 
juice.  The  secretion  of  the  pancreas  is  normally  augmented  on  the 
])assage  of  an  acid  fluid  through  the  pylorus,  and  if  the  acidity  of 
this  fluid  be  reduced  by  the  administration  of  alkalies,  a  much  smaller 
((uantity  of  })ancreatic  juice  is  thrown  into  the  intestine.  "^I'his  may 
again  render  the  digestion  less  complete,  although  the  greater  alkalinity 
of  the  intestinal  contents  tends  to  increase  the  efficiency  of  the  i)an- 
creatic  juice  already  secreted.  On  the  other  hand,  in  cases  of  hyi)er- 
acidity  of  the  stomach,  the  administration  of  alkalies  may  render  the 
contents  of  the  intestine  less  irritant,  and  thus  tend  to  allay  catarrh. 

The  alkalies  administered  in  medicinal  doses  seem  to  have  no  ell'ect 
on  the  intestinal  ])utref action,  for  the  double  sulphates  of  the  urine 
remain  unchanged  in  amount.  Kast  states  that  very  large  quantities 
(15  (J.,  2  oz.)  increase  the  putrefaction,  probably  through  nentrali/.ing 
the  disinfectant  gastric  juice. 

The  alkalies  have  been  believed  to  have  some  si)ecial  action  on  the 
Secretion  of  Bile;  thus,  it  has  been  sup])osed  that  they  rendered  the 
bile  more  alkaline  and  tended  to  dissolve  the  nuicus  contained  in  it, 
that  tlicy  |)rc\cntc(l  the  deposition  of,  and  cxcn  drssolxcd  gall-stones. 


HYDRATES  AND  CARBONATES  OF  THE  ALKALIES  539 

or  that  the>'  increased  the  secretion  of  bile  and  thus  swept  them  out 
of  the  2;all-bladder.  All  of  those  theories  have  been  overthrown  by 
the  investigations  of  Stadelmann  and  his  pupils,  who  have  shown  that 
alkaline  salts  do  not  increase  the  secretion  of  bile,  are  not  excreted  in 
it,  and  do  not  cause  any  change  in  its  reaction.  Any  effect  whicli  the 
alkaline  carbonates  or  hydrates  may  possess  in  hepatic  diseases  would 
therefore  seem  due  to  their  effects  in  the  duodenum. 

The  prolonged  administration  of  very  large  doses  of  the  alkaline 
carbonates  and  bicarbonates  causes  chronic  gastro-enteritis  in  animals, 
and  may  thus  prove  fatal  to  them. 

Absorption. — Both  hydrates  and  carbonates  disappear  rapidly  from 
the  stomach  and  intestine,  although  the  bicarbonate  of  soda  is  some- 
times credited  with  some  laxative  action;  this  may  not,  howe\er,  be 
due  to  the  same  causes  as  in  the  case  of  the  saline  cathartics.  All 
alkalies  are  neutralized  by  the  carbonic  acid  of  the  tissues  and  circulate 
in  the  blood  in  the  form  of  neutral  bicarbonates.  This  does  not  alter 
the  reaction  of  the  blood  as  ordinarily  understood;  thus  if  the  reaction 
with  litmus  be  taken  before  and  after  the  administration  of  alkali,  it  is 
found  to  be  unaltered.  On  the  other  hand  if  the  plasma  be  titrated  with 
an  acid,  more  is  required  after  an  alkali  has  been  administered,  provided 
the  carbonic  acid  is  driven  off  during  the  titration.  After  alkali  treat- 
ment then,  the  reaction  of  the  blood  is  unchanged  but.  the  alkali  avail- 
able for  the  neutralization  of  acid  is  augmented.  Even  when  the  alkali 
administered  has  been  neutralized  by  the  gastric  juice,  the  body  is 
rendered  more  alkaline,  because  a  certain  amount  of  the  carbonate  of 
the  blood  and  tissues  is  spared,  which  would  normally  have  been  used 
to  neutralize  the  hydrochloric  acid  before  it  could  be  reabsorbed.  This 
condition  of  augmented  alkalinity  can  only  last  a  short  time,  however, 
as  the  excretory  glands  at  once  proceed  to  remove  the  excess. 

It  was  formerly  supposed  that  the  alkalinity  (hydroxyl  concentra- 
tion) was  actually  increased  by  alkali  taken  by  the  mouth  and  this  was 
believed  to  influence  the  Metabolism,  because  many  oxidative  processes 
are  accelerated  outside  the  body  when  the  reaction  is  rendered  alkaline. 
But,  as  has  been  stated,  the  alkalinity  is  not  increased  in  the  tissues, 
but  only  the  available  alkali,  so  that  the  analogy  does  not  hold.  And 
examination  of  the  metabolism  under  alkali  shows  that  the. tissue  change 
is  ver\'  little  altered.  The  investigators  of  the  subject  have  generally 
confined  their  attention  to  the  effects  of  alkalies  on  the  products  of 
metabolism  excreted  in  the  urine,  and  have  found  the  total  nitrogen 
excreted  to  be  unchanged  in  a  considerable  nmnber  of  instances,  to  be 
slightly  increased  in  others,  and  to  be  diminished  in  a  few  indi\iduals. 
Even  in  those  cases  in  which  an  increase  is  observed  in  the  nitrogen 
of  the  urine,  it  does  not  always  indicate  an  increase  in  the  nitrogenous 
metabolism,  for  the  urine  is  often  increased  considerably  and  it  is 
evident  that  the  interchange  of  the  fluids  of  the  tissues  and  blood  is 
augmented;  so  that  the  increased  nitrogen  of  the  urine  is  accounted 
for  by  the  tissues  being  more  thoroughly  flushed  out  than  usual  by  the 
alkalies,  which  act  in  the  same  way  as  the  neutral  salts. 


540  SUBSTANCES  ACTING  AFTER  ABSORPTION 

Althouj^h  tlio  total  nitrogen  may  be  little  affected  by  the  adminis- 
tration ot"  the  alkalies,  the  form  in  Avhich  it  is  combined  in  the  urine 
and  in  the  blood  may  be  changed.  The  annnonia  of  the  urine  is  often 
diminished  in  amount,  while  the  urea  excretion  is  correspondingly 
augmented.  This  is  especially  marked  in  cases  in  which  excess  of 
acid  is  formed  in  the  tissues  or  absorbed  in  any  way,  and  is  explained 
by  the  fact  that  this  acid  is  ordinarily  neutralized  by  the  formation 
of  ammonia  in  the  tissues  (see  Acids).  When,  however,  fixed  alkali 
is  present  in  sufficient  amount,  as  when  the  carbonates  are  given,  the 
nitrogen  which  would  otherwise  have  been  excreted  as  ammonium 
salts,  is  formed  into  urea. 

■^'he  Uric  Acid  Excretion  imder  the  alkalies  has  been  the  subject  of 
numerous  researches,  but  in  the  great  majority  of  these  very  imper- 
fect methods  of  estimation  have  been  used.  In  the  few  cases  in  which 
satisfactory  methods  have  been  employed,  the  results  have  been  diver- 
gent, the  uric  acid  being  sometimes  decreased  and  sometimes  increased 
by  the  alkalies.  In  any  case  the  change  is  trifling  in  extent,  and  no 
inference  can  be  drawn  as  to  the  uric  acid  metabolism  from  it. 

As  regards  the  Oxidation  in  the  Tissues,  one  observer  found  the 
oxygen  a})sorbed  and  the  carbonic  acid  excreted  by  the  lungs  increased 
by  the  alkalies,  while  another  could  detect  no  change.  Another  method 
of  estimating  the  activity  of  the  oxidation  in  the  tissues  has  been 
used  by  Taniguti  and  Jawein,  who  both  found  that  in  man  the  neutral 
sulphur  of  the  urine  is  increased  by  the  alkalies  at  the  expense  of 
the  acid  sulphates;  they  interpret  this  as  indicating  a  diminution  of  the 
oxidation  of  the  tissues.  On  the  other  hand,  Heffter  and  Harnack, 
using  the  same  method,  came  to  the  conclusion  that  the  oxidation  in 
the  tissues  of  the  dog  is  increased  by  the  alkalies.  Others  have  found 
the  oxidation  of  fat  in  the  tissues  accelerated  hv  the  administration  of 
alkali. 

The  only  conclusion  which  seems  admissible  from  these  laborious 
investigations  is  that  the  tissue  waste  is  but  little  affected  in  amount 
by  the  administration  of  alkalies,  and  the  slight  changes  observed 
may  vary  not  only  in  different  species,  but  in  different  individuals, 
and  even  in  the  same  individual  at  different  times.  The  cause  of  this 
indi\idual  variation  may  be  differences  in  the  amount  of  acid  formetl 
in  the  tissues,  but  may  also  be  differences  in  the  local  effect  of  the 
alkalies  in  the  alimentary  tract. 

The  organism  ra])idly  frees  itself  from  the  excess  of  alkali  by 
Excreting  alkaline  salts.  This  excretion  occurs  chiefly  in  the  urine, 
whieh  becomes  less  acid,  or  even  alkaline  in  reaction,  and  in  the  latter 
event  contains  bicarl)t)nate  of  potassium  or  sodium.  As  a  general  rule, 
the  urine  soon  regains  its  acidity,  but  when  fairly  large  doses  are  given 
repeatedly,  its  reaction  may  be  kept  alkaline  constantly.  This  is  almost 
always  accomplished  in  man  by  the  administration  of  about  10-15  (t. 
(100-240  grs.)  of  sodium  carbonate  in  twenty-four  hours,  but  some 
persons  require  a  still  larger  cpiantity,  while  others  require  unicli  less. 
.\  Iciiiixtrary  jilkaliiic  reaction  lasting  2  'A  hours  nia\'  often  be  indnccd 


HYDRATES  AND  CARBONATES  OF   THE  ALKALIES  541 

hy  a  single  dose  of  2-3  G.  The  alkalies  have  the  same  efl'eet  on  the 
(>xeretion  of  the  salts  in  the  urine  as  the  neutral  salts — large  doses 
increase  the  sodium,  potassium,  and  chlorides  of  the  urine. 

The  injection  of  alkaline  carbonates  into  the  blood  induces  a  more  active 
secretion  from  the  bronchial  mucous  membrane,  according  to  Calvert,  while 
Rossbach  found  it  to  have  the  opposite  effect.  It  is  questionable  whether  the 
alkali  is  excreted  here. 

The  blood  of  rabbits  treated  with  alkalies  is  said  to  be  more  strongly  germi- 
cidal than  usual,  and  these  animals  show  greater  resistance  to  infection  with 
anthrax  bacilli.  These  effects  are  not  due  to  the  increased  alkalinity  of  the 
blood  directly,  for  serum  is  not  rendered  more  bactericidal  when  alkali  is  added 
to  it  in  test-tube  experiments. 

When  dilute  alkaline  solutions  are  applied  to  Isolated  Organs,  they  gen- 
erally increase  their  activity  for  a  time,  but  subsequently  weaken  it,  while 
strong  solutions  are  immediately  poisonous.  Thus  the  ciliary  movement  of 
epithelium  is  accelerated  by  dilute  alkalies,  the  sodium  salts  acting  more 
strongly  than  the  potassium  because  of  the  poisonous  K-ion  of  the  latter. 
The  developing  ova  of  sea  urchins  divide  more  rapidly  in  very  dilute  alkaline 
media,  but  the  resulting  cells  are  often  irregular  in  shape.  The  heart  also 
contracts  longer  and  more  strongly  when  it  is  perfused  by  a  chloride  of  sodium 
solution  rendered  alkaline  by  carbonate  of  soda  than  when  the  solution  is 
neutral.  Somewhat  stronger  solutions  increase  its  tonus  and  eventually  cause 
systolic  standstill.  The  arteries  are  contracted  in  the  same  w^ay  by  contact 
with  alkaline  solutions,  and  are  dilated  wdien  acids  are  perfused  through  them. 
Some  of  the  secretions  have  also  been  found  to  be  increased  by  the  pres- 
ence of  alkalies,  thus  the  glands  of  the  frog's  skin  are  stimulated  by  very 
dilute  alkaUne  solutions.  Loeb  has  recently  observed  that  the  presence  of  the 
— OH  ion  causes  frog's  muscle  to  absorb  considerable  quantities  of  water  from 
a  dilute  salt  solution,  while  on  the  other  hand.  Hamburger  states  that  the 
addition  of  small  quantities  of  alkahes  to  the  drawn  blood  reduces  the  size 
of  the  blood  cells.  Zoethout  states  that  some  unicellular  organisms  prove 
much  more  resistant  to  the  effects  of  the  withdrawal  of  oxygen  when  they  are 
placed  in  a  slightly  alkaline  medium,  and  suggests  as  an  explanation  that  the 
alkali  antagonizes  some  poison  formed  during  asphyxia. 

Strong  alkaline  solutions  destroy  aU  hving  tissues  with  which  they  come 
in  contact. 

Preparations. 

PoTAssii  Hydroxidum  (U.  S.  p.),  Potassa  Caustica  (B.  p.)  (KOH),  potas- 
sium hydrate,  caustic  potash — dry,  white  pencils  or  fused  masses,  deliquescent 
in  the  air  and  very  caustic. 

Sodii  Hydroxidum  (U.  S.  P.)  (NaOH),  sodium  hydrate  or  hydroxide,  caustic 
soda — white  translucent  pencils,  deliquescent  in  the  air  and  very  caustic. 

Liquor  Potassii  Hydroxidi  (U.  S.  P.),  Liquor  Potassce  (B.  P.),  solution  of 
potassium  hydrate,  about  5  per  cent.,  1  c.c.  (15  mins.);  B.  P.,  10-30  mins.,  to  be 
well  diluted. 

Potassii  Carbonas  (U.  S.  P.,  B.  P.)  (K2CO3),  a  white  granular  powder  of 
alkaline  reaction,  soluble  in  one  part  of  water.    1  G.  (15  grs.) ;  B.  P.,  5-20  grs. 

Sodii  Carbonas  (B.  P.)  (Na2CO3+10H2O),  colorless  crystals  with  an  alkaline 
reaction  and  taste,  soluble  in  about  two  parts  of  water.    0.3-2  G.  (5-30  grs.). 

Sodii  Carbonas  Monohjdratus  (U.  S.  P.)  (Na-iCOs+H-iO),  a  white  crystalline 
powder  without  odor  and  strongly  alkaline.    Dose,  0.25  G.  (4  grs.). 

Potassii  Bicarbonas  (U.  S.  P.,  B.  P.)  (KHCO3),  colorless,  transparent 
crvstals  with  a  saline,  slightly  alkaline  taste  and  soluble  in  three  parts  of  water. 
2  G.  (30  grs.);  B.  P.,  5-30  grs. 


542  SUBSTANCES  ACTING  AFTER  ABSORPTION 

SoDii  Hii  AUBUNAS  (U.  S.  P.,  I>.  P.),  (NiiHCOj),  a  white,  opaque  powder, 
with  a  cool,  alkahue  taste,  sohiblc  in  11  i)arts  of  water.  1  G.  (15  grs.);  B.  P., 
5-30  grs. 

Trocliisci  Sodii  Bicarbonntis  (U.  S.  P.),  each  contaiiiing  0.18  G.  (3  grs.). 

Lithii  Carbonas  (U.  S.  P.,  B.  P.)  (Li2C03),  a  light,  white  powder  with  an 
alkaline  taste,  soluble  in  80  parts  of  water,  but  more  soluble  in  carbonic  acid 
water.    0.5  G.  (7^  grs.);  B.  P.,  2-5  grs. 

Magnesia  (B.  P.),  Magnesii  Oxidum  (U.  S.  P.),  magnesia  (MgO)  2  G. 
(30  grs.);  B.  P.,  5-20  grs.  (repeated),  30-60  grs.  (single). 

Magnesii  Carbonas  (B.  P.,  U.  S.  P.),  3  G.  (45  grs.) ;  B.  P.,  5-GO  grs. 

These  act  as  aperients  in  large  doses  (p.  101)  but  are  largely  used  as  antacids. 
They  are  amorphous  powders  with  an  earthy  taste,  insoluble  in  water. 

Numerous  alkaline  mineral  waters  are  used  instead  of  the  pharmacopoeia] 
preparations,  but  as  a  general  rule  they  contain  only  very  small  quantities 
of  the  carbonates,  and  perhaps  act  more  through  the  large  amount  of  water 
than  through  their  alkaline  reaction. 

Therapeutic  Uses. — The  caustic  alkalies  are  used  Externally  to  a 
limited  extent  to  remove  growths,  such  as  warts,  from  the  skin.  For 
this  ])nrpose  the  potash  pencils  are  employed,  but  they  are  very  deli- 
quescent and  it  is  therefore  difficult  to  limit  their  action  to  one  spot, 
and  to  the  superficial  tissues.  When  the  desired  extent  of  cauteriza- 
tion has  been  o})tained,  the  ])art  should  be  washed  with  water,  or  with 
vinegar  or  some  other  dilute  acid.  The  carbonates  are  also  used 
externall.>'  to  some  extent,  chiefly  in  baths,  which  they  render  more 
irritant  to  the  skin,  and  in  which  they  tend  to  soften  and  remove  the 
superficial  horny  layers  of  the  epithelium  more  than  ordinary  water 
or  solutions  of  the  neutral  salts.  The  carbonates  are  also  api)lied 
in  strong  solution  or  as  a  paste  in  itching  skin  diseases,  and  often 
give  relief. 

Internally  the  alkaline  carbonates  and  more  rarely  the  solutions  of 
the  h>'drates  are  used  for  their  effect  on  the  stomach,  and  in  cases  of 
hyperacidity  relieve  the  pain  and  eructation  almost  instantly.  Even 
where  no  excessive  acidity  exists,  the  alkalies  are  often  beneficial 
in  small  quantities,  remo\'ing  distention  and  discomfort  without 
apparently  altering  the  digestion  to  any  marked  extent.  The  bicar- 
bonate of  ])otasli  is  more  frequently  used  for  this  purpose  than  the 
others,  and  the  carbonic  acid  liberated  in  the  stomach  may  be  of 
importance  in  the  action,  ^^4late^•cr  prejjaration  be  used,  it  ought 
to  be  w'ell  diluted  to  avoid  the  irritant  action  on  the  stomach  wall. 
Instead  of  these  alkalies,  the  carbonate  and  oxide  of  magnesium  may 
be  emi)l()yed  in  ])owder,  and  possess  the  advantage  of  not  causing 
any  irritation  and  at  the  same  time  ha^■e  some  aperient  action.  In 
cases  of  hyi^eracidity  the  alkalies  (antacids)  are  often  given  after 
meals,  while  when  the  secretion  does  not  seem  to  contain  an  excessive 
amount  of  acid  they  are  advised  before  meals,  and  may  then  be  com- 
biiu'd  with  other  stomachics,  such  as  bitters  or  volatile  oils. 

'i'he  alkalies  are  also  administered  for  their  effects  after  absori)tion, 
and  here  the  bicarbonate  of  potassium  is  most  frequently  i)rescribed, 
while  the  hydrate  solutions  are  rarely  used.^     Diabetes  was  formerly 

'  'V]\i:  ;if('tales,  citriites,  etc.,  may  also  bo  used  for  this  purpose  (p.  557). 


HYDRATES  AND  CARBONATES  OF  THE  ALKALIES  543 

trcaU'd  in  this  way,  in  the  hope  that  the  oxidation  in  tJie  tissues  would 
he  increased,  but  there  is  little  reason  to  suppose  that  the  alkalies  have 
any  such  effect  on  the  metabolism,  and  it  is  now  generally  accepted 
that  dial)etes  is  not  due  to  a  general  inability  of  the  tissues  to  oxidize. 
Experience,  too,  has  shown  that  the  glycosuria  is  not  lessened  appreci- 
ably by  the  use  of  the  alkalies.  When,  however,  diabetes  induces  an 
increased  acid  formation  in  the  tissues,  as  is  almost  invariably  the 
case  in  its  later  stages,  the  alkalies  are  of  undoubted  benefit  in  neutral- 
izing the  oxybutyric  acid  formed  and  thus  economizing  the  alkalies  of 
the  blood.  In  diabetic  coma,  temporary  improvement  may  very  often 
be  attained  by  the  use  of  large  doses  of  alkalies. 

In  gout,  rheumatism  and  the  "uric  acid  diathesis"  generally,  the 
alkalies  have  been  used  very  extensively,  partly  in  the  hope  that  the 
supposed  increased  combustion  in  the  tissues  would  destroy  a  larger 
amount  of  the  uric  acid,  and  partly  with  the  idea  that  the  uric  acid 
being  neutralized  in  the  tissues,  would  be  excreted  more  easily  and 
would  have  less  tendency  to  be  deposited.  There  are  some  grounds 
for  believing  that  the  alkaline  carbonates  are  of  benefit  in  gout  and 
rheumatism,  l)ut  neither  of  these  theories  seems  sufficient  to  explain 
their  effects,  for  no  increase  in  the  oxidation  has  been  shown  to  occur, 
and  on  the  other  hand  the  uric  acid  is  not  rendered  more  soluble  in 
the  blood  or  urine  by  the  quantities  of  alkali  used  in  therapeutics. 
In  the  present  position  of  the  uric  acid  question  and  of  the  pathology 
of  these  diseases,  howe^•er,  it  is  futile  to  attempt  to  explain  their  thera- 
jjeutics,  though  it  may  be  surmised  that  the  alkalies  may  influence  the 
formation  of  the  uric  acid  rather  than  its  excretion.  The  sodium  and 
})otassium  salts  have  been  used  very  largely,  and  the  lithium  carbo- 
nate has  been  advised  on  the  ground  that  lithium  urate  is  about  four 
times  as  soluble  as  sodium  urate.  Lithium  has  also  been  adminis- 
tered in  the  form  of  the  benzoate  and  salicjdate  in  these  diseases,  in 
order  to  combine  the  solvent  action  of  the  base  with  the  effects  of  these 
acids,  but,  as  in  so  many  other  similar  attempts,  one  of  the  chief  factors 
in  the  action  has  been  lost  sight  of;  much  too  small  quantities  of  the 
lithium  compounds  have  been  given  to  increase  the  available  alkali 
of  the  blood  appreciably,  and  besides  the  salicylate  and  benzoate  do 
not  increase  it  at  all,  as  they  are  neutral  salts.  The  lithium  salts  there- 
fore seem  to  be  superfluous  in  the  treatment  of  these  diseases,  since  they 
cannot  be  given  in  adequate  quantities  without  eliciting  lithium  poisoning 
(p.  515).  ]\Iore  benefit  is  derived  from  the  treatment  of  gout  and  rheu- 
matism by  the  alkaline  mineral  waters  than  by  artificial  preparations, 
and  this  is  especially  marked  when  patients  are  sent  to  the  mineral 
springs.  The  alkalinity  of  most  of  the  waters  is  very  slight,  and  the 
conclusion  is  inevitable  that  the  curative  agency  is  not  the  alkalinity, 
but  the  large  amount  of  fluid  taken,  together  with  the  dietetic  and 
other  hygienic  conditions. 

The  alkaline  preparations  are  also  largely  used  for  their  eft'ects  in 
the  urine.  In  cases  of  excessive  acidity  of  the  urine  leading  to  pain 
and  straining  during  micturition,  the  symptoms  are  relieved  by  these 


544  sriisrANCEs  acting  after  absorption 

(Iniirs  rendering  tlio  fluid  less  irritating,  and  this  relict"  is  fsju'cially 
marked  in  irrital)l('  conditions  of  tlic  Madder  and  urethra.  Thc\'  may 
also  he  of  \aliic  in  those  cases  })y  rendering  the  nuicus  more  soluhle  in 
the  bladder.  In  gravel  the  alkalies  also  give  relief,  and  this  has  been 
attributed  to  their  dissolving  the  uric  acid  m  the  urine,  or  rather  to 
their  keejiing  it  in  solution  in  the  form  of  salts.  In  order  to  attain 
this,  the  urine  would  have  to  be  rendered  alkaline,  or  at  least  neutral, 
and  relief  is  given  by  quantities  of  the  alkalies  which  are  quite  insuffi- 
cient to  do  this;  this  relief  in  gravel  results  from  the  amount  of  the 
urine  being  increased  while  its  acidity  is  lessened;  the  inflamed  surface 
of  the  bladder  is  thus  bathed  in  a  less  irritant  fluid  and  the  pain  is 
diminished.  Attempts  liave  even  been  made  to  flissolve  calculus  in  the 
bladder  or  in  the  kidney  by  treatment  with  the  alkalies,  but  there  is  no 
question  that  this  is  hopeless.  The  solution  of  the  alkalies  formed  in 
the  urine  is  extremely  dilute,  and  in  fact,  except  under  large  doses,  the 
reaction  is  not  even  constantly  neutral.  On  the  other  hand,  even  the 
alkaline  urates  are  by  no  means  very  soluble  bodies,  and  are  formed  only 
with  difficulty  except  in  strong  alkaline  solutions.  Again,  alkaline 
urine  is  very  liable  to  deposit  phosphates  in  the  bladder,  and  thus  rather 
to  increase  the  calculus  than  to  diminish  it.  Experience  has  shown 
conclusively  that  the  alkaline  treatment  does  not  remove  calculus, 
although  in  one  or  two  cases  it  is  stated  that  soft  calculi  broke  down  into 
fragments  under  it,  from  the  mucus  which  held  the  fragments  together 
being  dissolved.  The  pain  and  irritation  of  calculus  may  be  relieved 
to  some  extent,  however,  from  the  acidity  of  the  urine  being  lessened. 

The  alkaline  carbonates  are  also  prescribed  in  cases  of  jaundice  and 
gall-stone,  often  with  benefit.  This  is  not  due  to  their  acting  on  the 
bile  directly  in  all  probability,  for  it  has  been  shown  that  they  do  not 
affect  it  in  the  normal  animal ;  the  improvement  may  rather  be  ascribed 
to  their  lessening  duodenal  irritation. 

Sodium  chloride  solution  is  often  injected  intravenously  in  shock 
and  heart  failure,  and  it  is  found  beneficial  to  add  a  small  quantity 
of  sodium  bicarbonate  (1:10,000)  to  it.  Alkaline  solutions  should 
not  be  injected  hypodermically,  as  sloughing  has  been  observed  repeat- 
edly from  this  ])rocedure. 

The  bicarbonate  of  potassium  is  often  added  to  other  expectorant 
remedies  in  the  treatment  of  bronchial  catarrh  and  bronchitis,  and  is 
believed  to  increase  the  excretion  and  render  it  more  fluid  and  more 
easily  expectorated. 

The  alkaline  carbonates  may  be  given  as  antidotes  in  poisoning  with 
the  corrosive  acids,  although  magnesia  is  preferable,  because  it  is  less 
irritating  to  the  stomach. 

In  cases  of  Poisoning  with  the  caustic  alkalies,  the  treatment  con- 
sists in  the  administration  of  dilute  acids,  of  which  the  organic — 
acetic,  citric  or  tartaric — are  the  best.  The  first  is  most  readily  ob- 
tained in  the  form  of  vinegar.  No  attempt  should  be  made  to  ])ass 
the  stomach  tube,  as  it  is  liable  to  i)ass  through  the  <'orrode(l  wall  of 
the  (rso])hagus  or  stomach.  (lencral  measures,  such  as  central  ncr\ ous 
Stinuilants,  warmth,  etc.,  may  be  taken. 


ACETATES  AND  CITRATES  545 


Bibliography. 

Reichmann.     Arch.  f.  Verdauungskrankhciten,  i,  p.  44. 

Khigine.     Arch,  des  Scienc.  biologiques,  iii,  p.  461. 

Becker.     Ibid.,  ii,  p.  433. 

Glass.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxx,  p.  241. 

Salkowski  u.  Spilker.     Virchow's  Arch.,  cxvii,  p.  570. 

Taniguli.     Ibid.,  cxvii,  p.  581. 

Freudbcrg.     Virchow's  Arch.,  cxxv,  p.  566. 

Stadelmann.     Einfluss  der  Alkalien  auf  den  menschlichcu  StoffwcchscI,  1890. 

Jawein.     Ztschr.  f.  klin.  Med.,  xxii,  p.  43. 

Hegeler.     Arch.  f.  Hyg.,  xl,  p.  375. 

Calvert.     Joiirn.  of  Phys.,  xx,  p.  158. 

Passalsky  u.  Cruszeivitsch.     Maly's  Jahresber.,  xxiii  (1893),  p.  427. 

Hamack  u.  Kleine.     Ztschr.  f.  Biol.,  xxxvii,  p.  417. 

Zoethout.     Amer.  Journ.  of  Physiol.,  ii,  p.  220. 

Garret).     Ibid.,  iii,  p.  291. 

Piperazine  and  Quinic  Acid. 

Several  new  organic  compounds  have  been  introduced  of  late  years  as  solvents 
of  uric  acid  in  the  tissues  and  urine.     The  best  known  of  these  is  piperazine 

or  diethylendiamine   (NH</-itt^ Ptt">NH);  lycetol  and  lysidine  are  nearly 

related  bodies.  The  latest  remedy  is  quinic  acid,  C7H12O6,  which  is  found  in 
cinchona  bark  and  in  other  plants. 

Piperazine  and  its  alhes  dissolve  uric  acid  readily  in  the  test-tube,  more  rapidly 
than  lithium  or  borax,  which  are  often  prescribed  for  their  solvent  action; 
it  was  therefore  hoped  that  these  bases  would  prevent  the  deposit  of  uric  acid 
in  the  body  in  gout  by  forming  soluble  urates,  which  would  be  eliminated 
in  the  urine  But  very  little  of  the  piperazine  ingested  reappears  in  the 
urine,  and  this  quantity  is  too  small  to  have  any  solvent  action  on  the  uric 
acid.  And  what  does  escape  in  this  way  is  in  combination  with  the  stronger 
acids  and  not  with  the  uric  acid.  When  the  kidneys  are  inflamed  and  necrosed 
in  birds  through  the  action  of  chromic  acid,  the  uric  acid,  which  would  normally 
be  excreted  by  the  kidnej',  is  deposited  in  various  organs,  but  this  does  not  occur 
except  in  the  kidney  if  piperazine  is  administered.  This  has  been  used  as  an 
argument  in  support  of  the  treatment  of  gout  with  piperazine,  and  some  clinicians 
have  had  \Qvy  favorable  results  from  it,  while  most  have  been  disappointed. 
It  is  said  to  relieve  the  discomfort  due  to  the  passage  of  gravel  in  some  cases 
while  failing  in  others,  but  it  has  not  been  shown  to  be  of  any  value  in  the 
treatment  of  calculus,  and  the  urine  of  patients  treated  with  piperazine  has  no 
more  solvent  action  on  uric  acid  than  normal  urine.  Piperazine  seems  to  induce 
no  s}'mptoms  in  man  or  animals  even  when  administered  in  large  quantities. 

Quinic  acid  has  been  suggested  as  a  treatment  for  gout  on  the  erroneous 
theory  that  it  would  combine  with  glj'cocoll  in  the  body  and  thus  prevent  the 
formation  of  uric  acid.  As  a  matter  of  fact  it  has  no  effect  whatever  on  the 
amount  of  uric  acid  excreted.  In  short,  these  new  remedies  have  proved  no 
more   reliable  than  the  older  treatment  of  gout  and  the  "uric  acid  diathesis." 

Piperazine  is  given  in  solution  in  doses  of  1  G.  (15  grs.). 

XLIV.    ACETATES  AND  CITRATES. 

As  far  as  their  local  effects  are  concerned,  the  acetates  and  citrates  of  the 
fixed  alkalies  resemble  the  chlorides,  owing  any  effect  they  possess  to  the  salt- 
action.  In  the  tissues,  however,  they  are  oxidized  and  form  carbonates,  so 
that  the  effects  are  those  of  the  chloride  before  absorption,  and  those  of  the 
carbonate  subsequently.  The  oxidation  seems  to  proceed  rai:)idly,  and  is  very 
complete,  over  95  per  cent,  of  the  acetate  or  citrate  disappearing,  and  only  some 
2-3  per  cent,  bemg  excreted  unchanged  in  the  ui'ine.  The  available  alkali 
35 


546  SUBSTANCES  ACTING  AFTER  ABSORPTION 

of  tlic  hlood  is  iiRToasod  l)y  tlic  acctiites  as  by  the  carbonates,  and  the  urine 
is  increased  in  amount  and  is  less  acid  or  may  be  alkahnc. 

The  Acetates  seem  ahnost  devoid  of  specific  action — thej^  act  only  as  salts 
l)y  changinff  tlie  jihysical  properties  of  the  body  fluids,  or  as  alkalies  after  ab- 
sorption. The  otlier  members  of  the  acetate  series  have  some  action,  however, 
for  the  formate,  propionate,  butyrate  and  valerianate  of  sodium  have  been  shown 
to  be  very  weak  narcotics  when  they  are  injected  hypodermically  or  intra- 
venously; "this  is  especially  marked  in  the  case  of  the  butyrate.  Rather  more 
of  the  formate  escapes  unchanged  in  the  urine  than  of  the  acetate,  while  the 
others  are  apparently  entirely  oxidized.  The  butyrate  differs  from  the  acetate 
in  being  capable  of  taking  the  place  of  the  carbohydrates  and  fats  more  com- 
pletely, and  in  thus  leading  to  an  economy  of  the  nitrogenous  tissues  of  the 
body.  All  of  the  simpler  salts  of  this  series  are  equally  rapidly  absorbed  from 
the "  intestine,  but  the  (cnanthylate  and  the  caprylate  resemble  the  saline 
cathartics  in  being  very  slowly  absorbed. 

The  Lactates  resemble  the  acetates  in  being  almost  entirely  inactive,  but 
they  are  rather  more  slowly  absorbed.  They  are  oxidized  in  the  tissues  for 
the  most  part,  and  resemble  butyrates  in  limiting  the  nitrogenous  waste,  at  any 
rate  when  they  are  given  in  moderate  quantities.  Lactates  are  also  excreted  in 
the  vu'ine,  however,  in  small  quantity. 

The  Citrates  are  absorbed  more  slowly  than  the  acetates  or  chlorides  and  in 
sufficient  quantity  act  as  saline  purgatives.  The  doses  ordinarily  prescribed, 
however,  are  too  small  to  have  this  effect,  and  are  also-  insufficient  to  induce 
any  action  after  absorption  except  from  that  of  the  carbonate  formed.  Citrates 
form  indissociable  calcium  salts  and  when  they  are  injected  intravenously  they 
arrest  the  clotting  of  the  blood  and  weaken  the  heart  by  throwing  the  calcium 
out  of  action  (See  Calcium,  Oxalate). 

Preparations. 

Potassli  Acdds  (U.  S.  P.,  B.  P.),  a  crystalline  salt  of  pleasant,  saline  taste 
and  very  soluble  in  \vater.    2  G.  (30  grs.);  B.  P.,  15-60  grs. 
Potassu  CUras  (U.  S.  P.,  B.  P.)  (C3H40H(COOK)3)  1  G.  (15  grs.) ;  B.  P.,  15-60 

Sodii  Citrns  (U.  S.  P.)  (2C3H40H(COONa)3+ll.H20)  1  G.  (15  grs.).  Crystal- 
line salts  w^ith  a  cool  saline  taste,  readily  soluble  in  water. 

Potassii  CUras  Effervescens  (U.  S.  P.)  4  G.  (60  grs.). 

Sodii  citrotartras  Effervescens  (B.  P.)  60-120  grs. 

These  two  i)owders  contain  bicarbonate  of  sodium  antl  citi-ic  and  tartaric 
acids  and  effervesce  when  put  in  water. 

Acetate  and  citrate  of  i)otassium  have  been  largel}^  used  as  diuretics  and  in 
the  treatment  of  gout  and  rheumatism.  They  act  here  exactly  as  thc^  alkaline 
carbonates  and  bicarbonates,  but  have  the  advantage  of  not  neutralizing  the 
gastric  juice,  or  in  any  way  affecting  the  digestion  except  from  their  salt-action, 
which  may  be  minimized  by  exhibiting  them  in  dilute  solution. 


BlBLlOtlRAl'UY. 

Neubaucr.     Arch.  f.  cxp.  Path.,  Ixi,  p.  389. 
Mayer.     Arch.  f.  cxp.  Patli.  u.  Pharm.,  xxi,  p.  119. 
Weiskc  u.  Flcchsig.     Centrallil.  f.  Phys.,  1890,  p.  36. 
Mallevre.     Pfliiger's  Arch.,  xHx,  p.  460. 
Pohl.     Arch.  f.  cxp.  Path.  u.  Pharm.,  xxxi,  p.  289;    : 


xxxi,  p.  289;    xxxvii,  p.  413. 


XLV.    AMMONIA  AND  CARBONATE  OF  AMMONIA. 

.KiiiiiKinia    soliitioii    and    ( arhoiiate   of   aninioiiia    ilitlVT   coiisidcrablN' 
from  the  C()rrc'si)uii(liiig  hydrates  or  earbonates  of  the  fixed  alkalies  in 


AMMONI-A   AND  CARBONATE  OF  AMMONIA  547 

their  effects.  The  o;as  evaporates  ra])i(lly  from  its  watery  sohitions, 
and  the  carbonate  gi\es  oti'  ammonia  freely,  so  tliat  the  ett'ects  are 
\ery  simihir,  ahhoiigh  the  sohition  of  ammonia  is  much  the  more 
powerfuL  Owing  to  its  volatihty,  ammonia  penetrates  more  rapidly 
and  deeply  than  the  fixed  alkalies,  and  at  the  same  time  is  less  corro- 
sive and  less  enduring  in  its  effects.  Applied  to  the  skin  in  concen- 
trated solution,  it  may  corrode  to  some  extent,  but  ordinary  dilute 
preparations  act  merely  as  rubefacients,  like  the  volatile  oils.  Even 
concentrated  solutions  do  not  dissolve  the  epidermis  like  the  fixed 
alkaline  hydrates,  but  tend  to  penetrate  through  it  and  raise  blisters. 
When  inhaled,  the  irritation  of  the  nasal  mucous  membrane  causes  a 
reflex  stimulation  of  the  Aasomotor  centre,  and  consequent  contraction 
of  the  arterioles  and  augmented  blood-pressure,  while  the  respiration 
is  first  arrested,  and  then  becomes  deeper  and  fuller.  The  heart  may 
be  temporarily  slowed  by  inhibitory  reflexes.  Three  parts  of  ammonia 
in  10,000  of  air  cause  sneezing,  pain  in  the  nose,  and  tears,  when 
inspired  by  man,  and  5  parts  in  10,000  are  dangerous  when  inhaled 
for  some  time  (Lehmann).  Ammonia  is  not  absorbed  by  the  lungs, 
except  in  traces,  and  the  symptoms  arise  only  from  the  local  irritation 
and  subsequent  inflammation. 

Concentrated  solutions  cause  corrosion  of  the  mouth,  oesophagus  and 
stomach  similar  to  that  seen  in  poisoning  with  the  fixed  alkalies,  but 
some  of  the  vapor,  passing  into  the  respiratory  passages,  often  sets  up 
spasm  of  the  glottis,  or  such  swelling  of  the  mucous  membrane  of  the 
larynx  and  trachea  as  to  induce  asphyxia.  In  cases  of  ammonia  poison- 
ing, therefore,  the  symptoms  often  arise,  not  so  much  from  the  gastric 
corrosion  as  from  asphyxia,  and  death  may  occur  very  suddenly  from 
this  cause.  The  carbonate  of  ammonia,  when  swallowed,  also  causes 
slight  gastric  irritation,  and  in  larger  quantities  nausea  and  vomiting. 

After  absorption  ammonia  and  its  carbonates  are  rapidly  changed 
to  urea,  and  thus  dift'er  from  the  fixed  alkalies  in  not  increasing  the 
available  alkali  of  the  blood,  and  in  having  no  effect  on  the  urine  except 
to  increase  the  urea  and  thereby  cause  some  diuresis. 

The  carbonate  of  ammonia  stimidates  the  central  nerNous  system 
when  it  is  injected  into  the  blood  in  some  quantity,  but  it  has  no  such 
effect  when  absorbed  from  the  stomach.  (Cf.  Ammonium  Chloride, 
page  515.) 

Preparations. 

Aq^ia  Ammonice  Fortior  (U.  S.  P.),  a  28  per  cent,  solution  of  ammonia  in  water, 
and  Liquor  AmmonicE  Fortis  (B.  P.),  32J  per  cent.,  are  only  used  to  form  the 
other    preparations. 

Aqua  Ammonice.  (U.  S.  P.),  Liquor  Ammonioe  (B.  P.),  an  aqueous  solution 
of  ammonia  of  10  per  cent,  strength  by  weight. 

Spiritus  Ammonice  (U.  S.  P.),  an  alcoholic  solution  of  ammonia  containing 
10  per  cent,  of  the  gas  by  weight.    1  c.c.  (15  mins.). 

Spiritus  Ammonle  Aromaticus  (U.  S.  P.,  B.  P.),  Aromatic  Spirit  of  Harts- 
horn, Spirit  of  Sal  Volatile,  contains  ammonia  and  ammonium  carbonate 
along  with  several  volatile  oils  dissolved  in  alcohol.  2  c.c.  (30  mins.);  B.  P. 
20-40  mins.  (repeated),  60-90  mins.  (single),  in  a  glass  of  water. 


54S  SUIiSTANCKS  ACTIXd  AFTER   AHSORI'TION 

Linimcnium  Ammonm  (U.  S.  P.,  B.  P.),  ammonia  liniment,  volatile  lini- 
ment, contains  about  3.5  per  cent,  of  ammonia  (5  per  cent.  B.  P.). 

Ammomi  Carbonas  (U.  S.  P.,  B.  P.)  is  not  the  pure  carbonate,  but  a  mix- 
ture of  somewhat  varying  composition,  consisting  of  carbonate  (NH4HCO3) 
imd  carbamate  of  ammonia  (NH4NH2CO2).  It  releases  ammonia  in  the  air 
and  lias  therefore  its  pungent  taste  and  smell.  It  forms  translucent,  crystalline 
masses,  is  very  soluble  in  water  and  is  contained  in  the  aromatic  spirit  of  am- 
monia.   0.25  (4  grs.);  B.  P.,  3-10  grs.,  in  dilute  solution. 

Anunonia  is  contained  in  several  of  the  tinctures  of  the  B.  P.  (annnoniated 
tinctures)  aiul  in  the  Linimentum  Camphors  Ammoniatum,  etc. 

Therapeutic  Uses. — The  aqueous  solutions  of  ammonia  are  compara- 
ti\ely  rarely  employed,  altlioiiijh  the  strong  solution  has  been  ad\ise(l 
as  a  vesieant  in  eases  of  renal  disease,  in  which  eantharides  is  contra- 
indicated.  The  ammonia  solution  has  to  be  covered  by  a  watch-<ii;Iass 
in  order  to  prevent  its  evaporation,  and  is  said  to  be  more  painful 
than  other  vesicants.  The  liniment  is  used  as  a  rubefacient  in  l)ruises 
and  in  other  similar  conditions.  The  gas  arising  from  annnoninm 
carbonate  is  often  inhaled  in  cases  of  fainting  or  collapse,  in  order  to 
elicit  reflex  stimulation  of  the  medullary  centres.  The  ordinary 
"smelling  salts"  used  for  this  purpose  consist  of  the  carbonate  rein- 
forced with  some  of  the  strong  solution  and  flavored  with  oil  of 
lavender. 

The  aromatic  spirits  of  ammonia  and  the  carbonate  (in  solution) 
are  used  as  mild  gastric  stimulants  in  debility,  flatulence  and  alco- 
holism, and  are  very  eflScient  for  a  short  time.  Large  doses  of  the 
carbonate  (2  G.)  have  been  used  as  emetics,  and  do  not  cause  such 
l)rolonged  nausea  as  tartar  emetic  or  ipecacuanha. 

The  carbonate  of  ammonia  and  the  spirits  or  even  the  ordinary 
water  of  ammonia  are  often  given  in  cases  of  collapse  or  sudden  heart 
failure.  They  are  generally  administered  by  the  mouth  and  probably 
act  here  not  directly  on  the  heart  and  resi)iratory  centre,  as  has  been 
su])])osed,  but  reflexly  from  gastric  irritation.  They  have  also  been 
injected  subcutaneously  or  even  intravenously  for  this  i)urpose,  and 
here  the  local  action  may  be  reinforced  by  a  direct  action  on  the  medulla 
oblongata.  The  action  lasts  only  a  very  short  time,  l)ut  is  often  suflicient 
to  tide  the  ])aticnt  over  an  acute  collapse.  In  de])ression  fr(»m  nian\ 
dillVrent  causes  the  aromatic  spirits  of  ammonia  is  a  favorite  remedy, 
and  ])robal)ly  owes  its  value  to  its  gastric  action,  and  not  to  any  changes 
in  the  central  nervous  system.  The  carbonate  is  often  added  to  other 
expectorant  remedies  to  render  the  bronchial  mucous  excretion  more 
Ibiid.     (See  Anunonium  Chloride,  ])age  olo.) 

Strong  water  of  ammonia  is  ai)plied  locally  in  snake-bite  and  is 
j)o))ularly  believed  to  be  very  efficacious.  It  has  no  cfl'(>ct  on  the  tox- 
albumins  of  snake  poison,  and  j)robably  is  of  little  or  no  xahic  in  these 
cases. 


HiBT.IOflRAniY. 


Son  Aniiiimiiuiii  ('lildiidc,  imgc  41)S. 
l/ehinuun.      Ai<'li.  f.  Ilynit'iic,  v,  p.  1, 


ACIDS  549 


XLVI.     ACIDS. 

Some  acids  owe  their  activity  in  the  organism  ahnost  entirely  to 
their  acidity,  i.  e.,  to  the  hydrogen  ion,  which  is  much  more  powerful 
than  the  potassium  jon,  but  otherwise  stands  on  the  same  plane  with 
it;  those  acids  may  therefore  be  treated  of  together.  In  the  case  of 
many  other  acids,  such  as  prussic  or  saUcyUc  acid,  the  effects  of  the 
acidity  or  hydrogen  ion  are  insignificant  in  comparison  with  those  of 
the  rest  of  the  molecule  or  the  negative  ion,  and  these  are  treated  along 
with  their  salts. 

Action. — The  acids  owe  their  action  on  living  tissues  to  their  neu- 
tralizing alkalies,  to  their  withdrawing  water,  when  in  concentrated 
form,  and  to  their  precipitating  some  of  the  proteins,  more  especially 
the  globulins. 

JNIost  living  matter  is  neutral  or  slightly  alkaline  in  reaction,  and 
seems  to  be  incapable  of  existing  in  acid  media.  Exceptions  are  met 
with  in  some  of  the  moulds  and  in  other  vegetable  organisms  which 
live  in  somewhat  acid  solutions,  but  even  these  are  destroyed  by  more 
concentrated  solutions,  perhaps  because  the  acids  precipitate  their  pro- 
teins. Acids  are  therefore  Protoplasm  Poisons  and  antiseptics  of  some 
power.  Hydrochloric  acid  is  found  to  delay  the  growth  of  organisms, 
and  even  to  destroy  the  great  majority  of  the  less  resistant  forms  in 
0.2-0.3  per  cent,  solution,  or  in  the  percentage  in  which  it  exists  in 
the  gastric  juice.  The  others  vary  in  strength  largely  according  to 
their  acidity,  that  is,  according  to  the  number  of  hydrogen  ions,  or 
the  amount  of  dissociation.^  The  inorganic  acids  are  therefore  more 
powerful  as  a  general  rule  than  the  organic,  which  are  less  dissociated, 
and  among  the  latter  the  simpler  compounds  are  generally  more  active 
than  those  of  larger  molecule. 

When  sulphuric  or  nitric  acid  is  applied  to  the  Skin  in  concentrated 
form,  it  acts  as  a  powerful  caustic,  destroying  the  epidermis  and  pene- 
trating to  some  distance  into  the  skin  and  subcutaneous  tissues,  in 
which  it  causes  necrosis.  This  is  of  course  accompanied  by  great 
pain,  and  if  much  of  the  skin  is  attacked,  by  shock  and  collapse  and 
symptoms  similar  to  those  seen  in  severe  burns.  Sulphuric  acid  causes 
a  white,  later  a  brown  or  black  eschar,  nitric  acid  a  yellow.  Hydro- 
chloric acid  is  less  liable  to  cause  wholesale  destruction  of  the  skin, 
l)ut  penetrates  the  epidermis  and  raises  blisters.  The  organic  acids 
and  phosphoric  acid  are  still  less  irritant,  but  cause  redness  and  even 
blistering  when  applied  in  concentrated  solution.  Dilute  solutions 
of  the  acids  may  act  as  slight  irritants  to  the  skin,  and  often  cause 
a  feeling  of  stiffness  and  numbness,  perhaps  from  precipitating  the 
proteins. 

The  corrosive  action  of  the  acids  is  much  more  marked  when  they 

1  In  some  instances  the  toxicity  of  an  acid  is  not  proportional  to  its  dissociation,  how- 
ever, and  Loeb  has  shown  that  some  acids,  notably  the  slightly  dissociated  higher  organic 
acids,  penetrate  cells  more  readily  than  some  of  the  sini|)ler  ones  and  thus  more  tlian 
compensate  for  the  fewness  of  their  hydrogen  ions. 


f)')!)  Sl'BSTANCES  ACTING  AFTER  ABSORPTION 

arc  applied  to  the  less  resistant  Mucous  Membranes.  Even  small  quan- 
tities of  strong  sulphuric  acid  striking  tlic  eye  are  sufficient  to  destroy 
the  sight. 

In  the  Mouth,  (Esophagus,  and  Stomach,  the  corrosive  action  is  evi- 
denced hy  c()ni])lete  destruction  of  the  mucous  membranes  which  come 
in  contact  with  the  strong  acid.  The  oesophagus  and  stomach  may  be 
perforated,  and  this,  along  with  the  shock  and  collapse,  often  pro\'es 
immediately  fatal,  or  if  the  patient  recovers  temporarily,  tlie  erosions 
max-  give  rise  to  cicatricial  contractions  and  death  from  inanition. 
Hydrochloric  acid  and  the  stronger  organic  acids  are  capable  of  causing 
corrosion  of  tlie  mucous  membranes,  but  this  is  not  so  extensive  generally 
as  that  following  nitric  and  sulphuric  acid.  The  corrosion  from  acids 
(lifters  from  that  from  alkalies,  in  the  tissues  being  shrunken,  hard 
and  l)rittle,  while  after  a  caustic  alkali  they  are  soft  and  swollen  and 
ha\  e  a  slimy  soajn-  appearance. 

The  symi)toms  of  corrosive  acid  poisoning  are  intense  pain  in  the 
mouth,  throat  and  stomach,  vomiting  and  often  diarrhwa,  shock  and 
c()lla])se,  Avith  rapid,  weak  pulse  and  shallow  respiration.  The  tem- 
perature is  often  subnormal  and  death  occurs  in  the  course  of  a  few 
liours.  Wlu'ii  fuming  acids  are  swallowed,  and  especially  in  ])oison- 
ing  with  hydrochloric  acid,  the  irritant  \apor  passing  into  the  respira- 
tory ])assages  may  cause  spasm  of  the  glottis,  or  oedema  of  the  larynx, 
and  i)rove  immediately  fatal  from  asphyxia.  Even  one  part  of  hydro- 
chloric acid  vai)or  in  20,000  of  air  causes  sneezing  and  pain  in  the 
throat  and  chest  (Lehmann). 

Dilute  solutions  of  the  acids  have  a  characteristic  taste,  and  induce 
a  reflex  flow  of  saliva  and  an  astringent  feeling  in  the  mouth  and 
throat,  from  their  causing  a  coagulation  of  the  sui)erficial  layers  of 
proteins.  In  the  stomach  they  displace  any  weaker  acids  from  their 
ccmibinations  with  bases,  and  may  have  some  antiseptic  action,  but  do 
not  inffuence  the  amount  of  secretion  in  any  way.  The  gastric  juice 
is  normally  acid,  containing  about  0.2  per  cent,  of  free  hydrochloric 
acid,  and  this  acid  reaction  is  essential  to  the  action  of  i)ei)sin.  Other 
acids  may  rei)lace  the  hydrochloric  acid  in  digestion,  but  both  clinical 
ex])erience  and  experiment  point  to  hydrochloric  acid  as  the  most 
suitable  acid  for  use  in  tlie  stomach.  In  cases  of  deficient  gastric  secre- 
tion, the  administration  of  acids  increases  the  acidity  of  the  food  as  it 
j)asses  into  the  duodenum  and  may  thus  ])roinote  the  fornuition  of 
secretin  and  consequently  the  secretion  of  the  pancreas.  It  is  known 
that  food  is  allowed  to  pass  through  the  pyloric  sphincter  only  when  the 
reaction  is  distinctly  acid,  and  that  the  si)hincter  closes  again  when  the 
duodenal  mucous  membrane  is  stinnilated  by  acid;  when  the  food  in 
the  stomach  is  rendered  strongly  acid,  it  is  found  to  leave  the  stomach 
more  slowly,  thougii  the  mo\ements  of  the  organ  api)ear  to  l)e  more 
rapid  and  stronger  than  normally. 

'i'he  acids  are  absorbed  from  the  alimentary  canal  fairly  rai)idl>  in 
most  cases.  In  the  Blood  and  Tissues  tlicy  do  not  exist  as  acids  but 
as  salts,   for   tlir   reaction   of  the   bhxtd    must    remain   slightly   alkaline 


ACIDS  551 

throughout  Hfe,  and  if  sufficient  acid  be  given  to  neutralize  the  alkaHes 
of  the  body,  the  animal  dies  before  the  blood  becomes  neutral,  although 
after  deatli  it  may  be  found  to  be  acid.  The  means  provided  by  the 
economy  to  neutralize  acids  differ  in  different  animals;  in  the  herbivora 
the  fixed  alkalies  of  the  blood  and  tissues  are  called  upon  chiefly,  and  if 
more  acid  be  absorbed  than  can  be  neutralized  by  these,  the  animal 
dies;  in  the  carnivorous  animals  and  in  man,  a  further  protective 
mechanism  exists,  for  in  these  ammonia  is  liberated  by  the  tissues,  and 
serves  to  neutralize  the  acid,  and  thus  saves  the  fixed  alkalies.  The 
difference  is  relative  and  not  absolute,  however,  for  the  he^bi^'ora 
also  develop  some  ammonia,  and  the  carnivora  employ  some  of  the 
fixed  alkalies  to  preserve  the  normal  reaction  of  the  tissues.  Man 
appears  to  stand  midway  between  the  two  classes,  for  while  ammonia 
appears  in  the  urine  after  acid  absorption,  the  fixed  alkalies  are  also 
present  in  excess.  INIuch  larger  amounts  of  dilute  acids  may  therefore 
be  absorbed  without  serious  symptoms  by  man  and  by  the  carnivora 
than  by  the  herbivora.  The  explanation  of  this  difference  between  the 
flesh-eating  and  the  plant-eating  animals  is  to  be  found  in  the  nature 
of  their  food.  The  flesh-eaters  are  accustomed  to  the  formation  of  some 
acid  in  their  tissues,  because  the  alkalies  of  their  food  are  insufficient 
to  neutralize  the  acids  formed  by  the  oxidation  of  the  organic  matter, 
and  they  would  gradually  be  deprived  of  all  their  alkaline  salts,  therefore, 
were  they  not  protected  by  the  formation  of  ammonia.  On  the  other 
hand,  the  lierbivorous  animals  absorb  much  larger  quantities  of  the 
organic  salts  of  the  alkalies  in  their  food,  and  these  forming  carbonates 
in  the  body,  serve  to  neutralize  what  acid  is  formed  in  the  tissues.  In 
ordinary  circumstances,  therefore,  they  have  no  need  to  protect  the 
fixed  alkalies,  and  are  unprovided  with  any  mechanism  for  this  purpose. 
When  an  excess  of  acid  is  absorbed,  they  neutralize  it  by  means  of  the 
fixed  alkali  of  the  tissues  and  blood,  and  thus  lessen  the  available  alkali 
of  the  blood,  which  becomes  unable  to  carry  so  much  carbonic  acid 
from  the  tissues  to  the  lungs.  Thus  in  acid  poisoning  in  rabbits,  the 
alkali  of  the  blood  has  been  found  to  be  so  greatly  reduced  that  instead 
of  containing  some  twenty-five  volumes  of  carbonic  acid  per  cent,  of 
blood,  it  carried  only  two  volumes  per  cent,  or  very  little  more  than 
could  be  dissolved  in  the  same  amount  of  water.  When  this  occurs, 
the  tissues  are  unable  to  rid  themselves  of  their  carbonic  acid,  and  a 
series  of  symptoms  follow,  commencing  in  deep,  labored,  rapid,  after- 
wards shallow,  respiration;  the  heart  is  weak,  a  condition  of  collapse 
follows,  and  eventually  the  respiration  ceases,  the  heart  continuing  to 
beat  for  some  time  longer.  The  injection  of  sodium  carbonate,  even  in 
the  last  stage  of  intoxication,  is  followed  by  rapid  recovery,  from  more 
alkali  being  supplied  to  the  blood  and  tissues,  while  other  carbonates 
are  not  so  useful,  owing  to  the  action  of  the  basic  ion.  In  carnivora 
and  man,  the  absorption  of  dilute  acids  does  not  alter  the  available 
alkali  of  the  blood  to  any  marked  degree,  and  no  serious  symptoms 
arise  from  this  cause. 
The  salts  formed  in  the  blood  and  tissues  after  the  absorj)ti()n  of 


552       SUBSTANCES  ACTING  AFTER  ABSORPTION 

acids  are  rapidly  Excreted  by  the  kidneys,  which,  however,  retain  as 
nnitli  alkaU  as  i)ossible  in  the  body  and  thus  excrete  the  salts  in  an 
acid  t'oriii.  Hence  there  arises  hi  some  cases  irritation  of  the  kidneys, 
with  albumin,  and  even  blood,  in  the  urine,  which  is  rendered  more 
acid  than  usual  and  causes  a  sensation  of  heat  and  smarting  in  the 
bladder  and  urethra.  In  the  herbivora  the  reaction  changes  from 
alkaline  to  strongly  acid,  and  large  c^uantities  of  the  salts  of  the  alka- 
lies appear,  while  in  the  carnivora  some  increase  in  the  sodium  and 
potassium  of  the  urine  occurs  along  with  a  much  greater  increase  in 
the  ammonia.  The  total  nitrogen  is  somewhat  increased  from  the 
large  amount  of  ammonia,  but  the  urea  is  slightly  decreased.  Some 
authors  have  found  an  augmented  excretion  of  lime  in  the  urine,  while 
others  state  that  it  is  less  than  usual. 

Not  infrequently  fatty  degeneration  of  the  heart,  liver,  muscles  or  kidney 
has  been  observed  in  corrosive  acid  poisoning,  when  the  patient  survived  for 
a  few  days,  and  Fraenkel  and  Reiche  found  a  form  of  necrosis  of  the  renal 
cells  in  these  cases.  These  changes  are  not  due  to  free  acid  in  the  blood,  but 
their  exact  cause  has  not  been  satisfactorily  determined. 

The  prolonged  treatment  of  animals  with  acids  has  been  found  to  be  fol- 
lowed by  anannia  and  loss  of  flesh  and  strength,  which  are  probably  attribu- 
table to" the  disturbance  of  the  digestion  and  not  to  any  specific  action  of  the 
acids. 

Acids  applied  directly  to  the  living  tissues  lessen  their  vitalitj^,  and  unless 
there  is  sufficient  alkali  present  to  neutralize  them,  soon  destroy  it  entirely. 
In  some  cases  the.v  tend  to  cause  a  temporary  increase  in  activity  at  first;  thus 
the  ciUa  of  ciUated  epithelium  have  been  found  to  move  more  rapidly  at  first 
in  very  dilute  acids  and  then  to  cease  all  movement,  while  muscle  seems  to  be 
rendered  weaker  and  less  ii'ritable  at  once.  As  in  the  case  of  alkalies,  Loeb 
finds  that  dilute  acid  causes  muscle  to  imbibe  more  water  than  salt  solution 
does,  and  Hamburger  finds  that  the  red  blood  cells  are  increased  in  size  by  the 
addition  of  small  (juantities  of  acid  to  the  blood  outside  the  body.  The  frog's 
heart  is  weakened  and  dilated  by  the  addition  of  acid  to  a  perfusing  solution, 
and  the  muscular  wall  of  the  vessels  also  relaxes.  The  addition  of  acids  to  the 
blood  tends  to  agglutinate  the  red  cells  and  to  form  methamoglobin. 

Therapeutic  Uses. — The  acids  are  used  in  medicine  only  to  a  limited 
extent,  and  most  of  the  official  preparations  might  well  be  dispensed 
with. 

They  may  be  employed  to  give  flavor  to  draughts  in  fever  and  in  the  thirst 
of  diabetes,  the  most  popular  forms  being  those  formed  from  fruits,  such  as 
lemons,  limes,  or  grapes.  The  taste  is  due  to  the  sugars,  acids  and  volatile 
oils  of  the  fruits,  and  is  modified  by  the  presence  of  inert  colloid  substances, 
such  as  the  i)ectins.  The  acids,  of  which  citric,  tartaric  and  malic  are  the  chief, 
are  very  important  factors  in  the  effect,  for  if  these  be  neutralized,  the  fruit 
juices  become  insipid,  and  do  not  quench  thirst  so  thoroughly.  The  so-called 
grape  cure,  in  which  very  large  quantities  of  grapes  are  eaten,  owes  most  of  its 
value  to  the  large  amount  of  water  taken,  although  the  acids  and  salts  may  act 
as  ai)erieuts  in  the  same  way  as  the  saline  cathartics.  Instead  of  the  fruit 
juices,  carbonic  acid  waters  may  be  advised,  and  occasionally  other  acids,  such 
as  phosphoric  or  sulphuric,  are  prescribed  to  give  flavor. 

Acids  are  also  used  in  certain  forms  of  dyspep.sia  in  which  the 
liN'drocliInric  ;i(id   of  the  stomach  is  deficient.      Ih-drocliioric  acid   is 


ACIDS  553 

most  frequently  prescribed  for  this  purpose,  althougli  nitric  and  nitro- 
hydrochloric  acids  have  also  some  reputation;  the  hydrochloric  acid 
is  certainly  more  efficient  than  these  in  test-tube  experiments  on 
digestion.  The  forms  of  (lyspei)sia  thus  treated  are  generally  those 
arising  from  a  sedentary  life  or  in  the  course  of  convalescence,  and 
the  acids  are  often  prescribed  along  with  the  bitter  stomachics  and 
are  to  be  taken  about  half  an  hour  before  meals.  Irritation  of  the 
stomach,  or  hyperacidity  of  the  gastric  juice,  is,  of  course,  a  contra- 
indication. 

Acid  may  also  be  used  to  make  the  urine  acid,  and  thus  to  render  it 
less  favorable  to  the  growth  of  microbes.  For  this  purpose  the  acid 
sodium  phosphate  is  used;  this  salt  is  very  often  given  along  with 
hexamethylentetramine,  which  acts  only  in  acid  urine  (p.  1(30). 

In  cases  of  alkaline  poisoning,  the  acids  are  the  natural  treatment; 
the  organic  acids  should  be  preferred  for  this  purpose,  as  they  are  less 
liable  to  cause  additional  corrosion,  and  acetic  acid  in  the  form  of 
^'inegar  is  more  likely  to  be  at  hand  than  any  other. 

In  every  case  in  which  acids  are  prescribed  internally,  they  have 
to  be  given  largely  diluted,  as  otherwise  they  irritate  the  throat  and 
stomach.  They  are  taken  through  a  glass  tube,  in  order  to  prevent 
as  far  as  possible  their  action  on  the  teeth. 

Strong  acids  have  some  effect  in  arresting  hsemorrhage  (styptics)  when 
applied  directly  to  the  bleeding  point,  but  are  much  inferior  to  some  of  the 
metallic  salts,  such  as  the  iron  perchloride. 

Externally,  the  acids  are  used  to  some  extent  as  corrosives,  strong  nitric 
acid  being  not  infrequently  used  to  destroy  small  tumors,  to  cauterize  the  os 
uteri  and  for  similar  objects.  Its  action  is  more  easily  localized  than  that  of 
potash  and  on  the  other  hand  is  more  powerful  than  the  metallic  salts,  such 
as  silver  nitrate  and  zinc  chloride.  In  dilute  solution,  they  are  sometimes 
applied  to  the  skin  to  lessen  excessive  local  sweating  and  diluted  vinegar  is 
often  used  to  sponge  fever  patients. 

In  cases  of  corrosive  Poisoning  with  acids,  the  first  indication  is  to 
neutralize  the  acids  as  far  as  possible  by  giving  alkalies.  These  ought 
not  to  be  in  themselves  corrosive,  and  the  best  antidote  is  therefore 
the  insoluble  magnesia  and  magnesium  carbonate.  Lacking  these, 
the  most  readily  accessible  alkali  is  the  best,  and  the  lime  may  be 
scraped  from  the  walls  or  ceilings,  or  chalk,  soap,  or  wood  ashes  may 
be  given.  The  walls  of  the  stomach  and  oesophagus  may  also  be  pro- 
tected by  giving  milk  or  white  of  egg,  or  the  acid  may  be  rendered 
less  corrosive  by  diluting  it  with  large  quantities  of  water. 

Bibliography. 

Waller.     Arch.  f.  exp.  Path.  u.  Pharm.,  vii,  p.  148. 
Salkowski.     Virchow's  Arch.,  Iviii,  p.  1. 
Jacquet.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxx,  p.  311. 
Hahn.     Virchow's  Arch.,  cxxxvii,  p.  597. 
Hiibner.     Fortschritte  der  Med.,  xii,  p.  163. 
Fracnkel  u.  Reiche.     Virchow's  Arch.,  cxxxi,  p.  130. 
Wroblewski.     Zcitschr.  f.  phys.  Chem.,  xxi,  p.  1 
Runge.     Arch.  f.  exp.  Path.  u.  Pharm.,  x,  p.  324. 


551       SUBSTANCES  ACTING  AFTER  ABSORPTION 

Freudbcro-     Virchow's  Arch.,  cxxv,  p.  566. 
Dunlop.     Journ.  of  Phj's.,  xx,  p.  82. 

Loeb.     Pfliif^cr's  Arch.,  Ixix,  p.  1;  Ixxiii,  p.  422;  Biochcm.  Ztschr.,  xv,  p.  254. 
Wintcrberg.     Ztschr.  f.  phys.  Chem.,  xxv,  p.  202. 
Limbeck.     Ztschr.  f.  klin.  Med.,  xxxiv,  p.  419. 
Loewi/  u.  Munzer.     Arch.  f.  [Anat.  u.]  Phys.,  1901,  p.  81. 
Spiro.     Beitriige  z.  phys.  und  path.  Cheniie,  i,  p.  269. 
Cannon  and  Hedblom.     Amor.  Jour.  Med.  Sci.,  October,  1909. 

Compare  AlkaUnc  Hydrates  and  Carbonates.  For  the  specific  effects  of  the  anions 
of  the  acids,  see  chlorides,  phosphates,  acetates,  oxalates,  etc. 

Sulphuric  Acid  is  one  of  the  most  corrosive  acids  wlioii  it  is  applied  in  con- 
centrated form,  and  often  induces  complete  chari-ing  of  the  tissues,  and  a  coal- 
black  slough. 

Acidum  Sidphuricum  Dilutum  (U.  S.  P.,  B.  P.)  contains  10  i)er  cent,  of  abso- 
lute sulphuric  acid.    2  c.c.  (30  mins.);  B.  P.,  5-20  mins. 

Acidum  Sidphuriaim  Aromaticum  (U.  S.  P.,  B.  P.)  is  an  alcoholic  solution 
flavored  A\'ith  ginger  and  cinnamon.  The  U.  S.  P.  preparation  contains  20 
per  cent.,  the  B.  P.  preparation  11.4  per  cent,  of  sulphuric  acid.  1  c.c.  (15  mins.) ; 
B.  P.,  5-20  mins.,  in  a  glass  of  water. 

The  sulphuric  acid  preparations  are  hot  largelj-  used.  The  aromatic  acid  is 
sometimes  given  as  a  prophjdactic  and  remedy  in  lead  poisoning,  but  it  is  prob- 
ably of  little  value  here. 

Nitric  Acid  is  equal  or  superior  to  sulphuric  in  its  corrosive  action.  It  stains 
the  skin  and  tissues  a  bright  yellow  or  yellowish-brown,  and  this  serves  to 
distinguish  cases  of  poisoning  under  the  two  acids. 

Acidum.  Nitricum  (U.  S.  P.,  B.  P.)  contains  68  per  cent,  of  absolute  nitric 
acid  (HNO3)  (B.  P.  70  per  cent.). 

Acidum  Nitricum  Diluium  (U.  S.  P.,  B.  P.)  contains  10  per  cent,  by  weight 
of  absolute  nitric  acid.    2  c.c.  (30  mins.);  B.  P.,  5-20  mins. 

A  glass  rod  dipped  in  concentrated  nitric  acid  is  used  as  a  corrosive.  The 
dilute  acid  has  been  advised  in  dyspepsia,  but  is  generally  considered  inferior 
to  hychochloric  acid,  and  has  been  shown  to  be  much  less  efficient  in  artificial 
digestion.  It  has  also  some  reputation  in  certain  liver  diseases,  and  is  occa- 
sionall.y  used  in  some  intestinal  conditions  accompanied  by  diarrhoea. 

Hydrochloric  Acid  is  less  corrosive  than  the  two  preceding  acids,  and  tends 
to  cause  blistering  on  the  skin  rather  than  necrosis.  It  may  cause  actual  loss 
of  substance,  however,  when  applied  to  the  mucous  membranes  in  concentrated 
form,  and  stains  the  mouth  a  whitish  color. 

Acidum  Hydrochloricum  Dilution  (U.  S.  P.,  B.  P.),  contains  10  per  cent, 
of  hydrochloric  acid  gas.  1  c.c.  (15  mins.);  B.  P.,  5-20  nuns,  in  a  glass  of 
water. 

The  diluted  acid  is  prescribed  in  dyspepsia  in  which  there  seems  a  deficiency 
of  the  natural  acid  secretion.  In  cases  of  diarrhcea  in  which  excessive  putre- 
faction of  the  intestinal  contents  is  present,  it  may  be  of  benefit  when  pre- 
scribed along  with  other  drugs;  this  action  is  probal)ly  explained  by  its  dis- 
infecting the  stomach  contents,  as  the  hj'drochloric  acid  of  the  gastric  seci'etion 
normally  does;  for  the  double  sulphates  of  the  urine  certainly  tliminish  under 
its  use  in  many  cases.  It  is  said  that  hydrochloric  acid  i)revents  the  lactic 
fermentation  in  1  :  1000  dilution,  and  that  in  addition  to  its  action  on  the 
digestive  fcnnents  it  incn^ases  the  peristalsis  of  the  stomach. 

BlHLIOCIJ.M'HV, 

Cohn.     Zts.  f.  phys.  Chem.,  xiv,  j).  74. 
Ilirschfdd.      PlUiner's  Arch.,  xlvii,  p.  510. 
Kasl.     Maly'.s  .laiircshericht,  18S9,  xix,  p.  271. 
Schnvlc.     Ztschr.  f.  klin.  Med.,  xxix,  p.  (17. 
Lihmiiiiit.     Arch.  f.  Hytjicuc,  v,  p.  1. 


ACIDS  555 

Nitrohydrochloric  Acid  is  formed  by  inixiug  hydrochloric  and  nitric  acid, 
andcoutiiins  not  only  the  original  acids,  but  a  number  of  decomposition  prod- 
ucts, such  as  chlorine,  nitroxychloride  (NOCl)  and  nitrous  acid.  The  strong 
acid  (aqua  regia)  is  the  most  powerful  solvent  and  oxidizing  agent  known, 
dissolving  such  refractory  metals  as  platinun:i  and  gold. 

The  diluted  acid  alone  is  used  in  therapeutics  (Dose  15  mins.)  and  has  some 
reputation  in  liver  diseases  and  jaundice.  This  appears  to  be  a  survival  of  the 
ancient  doctrine  of  signatures,  according  to  which  the  therapeutic  value  of  a 
drug  was  indicated  by  its  color,  shape  or  other  similar  qualities;  thus  red- 
colored  roots  were  used  for  diseases  of  the  blood,  and  yellow  fluids,  such  as 
nitrohvdrochloric  acid,  in  jaundice,  a  yellow  disease. 

Phosphoric  Acid  is  much  less  corrosive  and  irritant  than  the  other  mineral 
acids,  but  in  large,  concentrated  doses  may  cause  gastro-enteritis.  It  has 
been  used  to  some  extent  to  form  cooling  draughts  in  fever.  It  has  also  been 
prescribed  in  various  cachectic  conditions  on  the  theory  that  these  were  due  to 
a  deficiency  of  phosphates  in  the  food  and  tissues;  but  it  has  never  been  shown 
to  be  of  aiiy  benefit  in  these.  The  acidity  of  the  urine  arises  from  the  excretion 
of  acid  phosphates  for  the  most  part,  and  may  be  increased  by  the  administra- 
tion of  Sodii  Phosphas  Acidus  (B.  P.),  NaH,P04.  Tliis  consists  of  colorless 
crystals  with  an  acid  saline  taste,  readily  soluble  in  water.     Dose,  30-60  grs. 

The  Organic  Acids  have  a  much  less  marked  local  action  than  the  inorganic, 
causing  little  or  no  corrosion  unless  when  applied  to  mucous  surfaces  in  very 
concentrated  form.  They  are  absorbed  as  salts  of  the  alkalies,  but  do  not  as  a 
general  rule  reduce  the  available  alkali  of  the  blood  or  render  the  urine  more 
acid,  because  they  are  oxidized  to  carbonates  in  the  tissues.  Oxalic  acid  is  the 
chief  exception  to  this  rule,  but  the  specific  action  of  the  oxalates  is  powerful 
enough  to  conceal  the  acid  action  to  a  great  extent. 

Acetic  Acid  applied  in  concentrated  solution  to  the  skin  causes  irritation 
and  congestion  and  eventually  blistering,  but  does  not  induce  necrosis  except 
of  the  most  superficial  layers.  The  congestion  is  often  followed  by  marked 
pallor  instead  of  by  blistering;  and  tliis  has  been  explained  by  contraction 
of  the  vessels,  but  may  be  due  to  a  precipitation  of  the  proteins  of  the  skin. 
In  the  mouth  and  stomach  it  acts  as  an  irritant,  causing  vomiting,  great  pain, 
collapse  and  even  death;  the  epithelium  is  found  thickened  and  occasionally 
contains  haemorrhages .  Dilute  acetic  acid  (vinegar)  has  little  effect  apart 
from  its  acid  taste,  and  is  used  largely  as  a  flavoring  agent  and  condiment. 
The  prolonged  use  of  large  quantities  may,  however,  give  rise  to  gastric  irri- 
tation and  to  loss  of  appetite  and  weight. 

Acidum  Aceticum  (U.  S.  P.,  B.  P.)  contains  36  per  cent,  of  absolute  acetic 
acid  U.  S.  P.,  33  per  cent.  B.  P.  •         ■ , 

Acidum  Aceticum  Dilutum  contains  6  per  cent,  of  absolute  acetic  acid 
U.  S.  P.,  5  per  cent.  B.  P.    2  c.c.  (30  mins.);  B.  P.,  ^-1  fl.  dr. 

Acetic  acid  is  sometimes  applied  to  the  skin  as  a  slight  local  irritant  in  con- 
tusions, and  in  very  dilute  solutions  to  cool  the  surface  and  to  prevent  excessive 
local  perspiration.  It  has  been  used  as  a  styptic  in  slight  haemorrhage,  and  may 
be  inhaled  for  this  purpose  in  epistaxis.  Vinegar  is  also  inhaled  in  cases  of 
fainting,  in  order  to  induce  reflex  stimulation  of  the  vasomotor  centre  through 
irritation  of  the  nostrils.  In  cases  of  poisoning  with  alkalies  vinegar  is  often 
the  most  convenient  acid,  and  in  addition  is  less  likely  to  do  harm  than  the 
inorganic  acids. 

Acetic  acid  itself  is  not  used  as  a  corrosive,  but  one  of  its  derivatives,  trichlor- 
acetic acid  (CC'UCOOH),  U.  S.  P.,  has  been  employed  with  good  results. 

Formic  Acid  resembles  acetic  acid  in  most  points,  except  that  it  is  more 
volatile  and  more  irritant,  that  less  of  it  is  oxidized  in  the  tissues,  and  thtit 
given  in  large  quantities  it  is  said  to  induce  nephritis.  It  is  quite  useless  in 
therapeutics. 

The  other  acids  of  the  acetic  acid  sei-ies  resemble  acetic  acid  in  then-  eflects, 
but  become  less  irritant  as  they  become  more  complex  and  less  (\isily  dissociated. 


556       SUBSTANCES  ACTING  AFTER  ABSORPTION 

Lactic  Acid  resembles  acetic  acid  in  its  behavior  in  the  organism.  It  was 
suggested  at  one  time  that  sleep  following  muscular  exertion  was  due  to- the 
lactic  acid  formed  in  the  muscles,  and  this  acid  was  therefore  recommended  as  a 
hypnotic,  but  has  been  shown  to  be  of  no  value  for  this  purpose.  Rickets, 
rheumatism  and  other  tliseases  were  also  at  one  time  attributed  to  the  excessive 
formation  of  lactic  acid  in  the  tissues,  but  this  theorj-  is  only  of  historical  interest. 
Lactic  acid  has  been  used  recently  as  a  caustic  application  to  malignant  ulcers 
and  diphtheritic  membranes. 

Oxalic  Acid  is  frequently  used  as  a  poison  by  suicides,  either  as  such  or  as 
the  acid  potassium  salt  (salt  of  sorrel  or  essential  salt  of  lemons).  Poisoning 
has  repeatedly  occurred  from  oxalic  acid  having  been  mistaken  for  magnesium 
sulphate,  which  it  resembles  in  appearance.  The  symptoms  are  those  of  acid 
poisoning,  along  with  the  specific  effects  of  the  oxalates.  Oxalic  acid  is  not 
used  in  therapeutics. 

Tartaric  Acid  induces  symptoms  of  gastric  irritation  when  taken  in  large 
doses,  and  has  been  the  cause  of  fatal  poisoning  in  a  few  cases.  It  is  slowly 
absorbed,  and  some  of  it  escapes  combustion  in  the  tissues  and  is  excreted  in 
the  urine  in  the  form  of  acid  tartrate.    (See  Tartrates,  page  105.) 

Acidum  Tartaricum  (U.  S.  P.,  B.  P.)  (H2C4H4O6),  colorless  crystals  very 
soluble  in  water.    0.5  G.  (7|  grs.) ;  B.  P.,  5-20  grs. 

Tartaric  acid  is  prescribed  with  the  carbonates  and  bicarbonates  to  form 
effervescent  draughts;  the  tartaric  acid  ought  to  be  shghtly  in  excess  in  order 
to  lend  its  pleasant  acid  taste,  the  usual  proportion  being  about  eight  parts 
of  acid  to  seven  parts  of  sodium  bicarbonate.  These  effervescent  mixtures 
formed  with  the  tartrates  act  as  saline  cathartics  in  large  doses  (see  page  106). 
Tartaric  acid  may  be  prescribed  in  dilute  solution  with  sugar  and  a  drop  of 
volatile  oil  as  a  lemonade,  which  is  cheaper  than  that  formed  with  citric  acid. 

Citric  Acid  resembles  tartaric  acid  in  its  action,  but  appears  less  irritant, 
and  no  case  of  serious  poisoning  is  recorded  from  its  use.  It  is  slowly  absorbed 
like  tartaric,  but  seems  to  be  almost  entirely  oxidized  in  the  tissues. 

Acidum  Citricum  (U.  S.  P.,  B.  P.)  (H3C6H5O7+H2O)  resembles  tartaric 
acid  in  its  properties  for  the  most  part.    0.5  G.  (7|  grs.) ;  B.  P.,  5-20  grs. 

Syrupus  Acidi  Citrici  (U.  S.  P.)  is  ordinary  syrup  to  which  1  per  cent,  of 
citric  acid  and  tinctm-e  of  lemon-peel  have  been  added,  and  is  used  only  as  a 
flavor. 

Citric  acid  and  the  citrates  when  added  to  drawn  blood  prevent  clotting  by 
combining  with  the  calcium  in  a  practically  non-dissociating  salt.  When 
administered  by  the  mouth  it  has  no  such  effect  on  the  circulating  blood,  and 
its  use  to  lessen  clot  formation  in  the  body  is  based  on  erroneous  observation. 

Citric  acid  is  used  to  form  lemonades  and  effervescent  draughts.  For  lemonade 
2-4  parts  of  citric  acid  may  be  dissolved  in  1000  parts  of  water,  some  sugar 
and  a  few  drops  of  volatile  oil  being  added.  For  effervescent  solutions  about 
iS  parts  of  the  acid  may  be  prescribed  along  with  7  parts  of  bicarbonate  of  soda, 
with  directions  to  dissolve  the  two  powders  separately,  mix  the  solutions  and 
drink  while  effervescing.  In  large  quantities  this  mixture  acts  as  a  saline 
cathartic;  in  smaller  quantities  it  may  be  used  to  increase  the  alkali  of  the 
blood,  and  to  render  the  urine  less  acid. 

Lime  juice  and  lemon  juice,  which  contain  considerable  amounts  of  free 
citric  acid,  are  generallj^  preferred  to  the  pure  acid  for  lemonades  to  quench 
the  thirst.  Lime  juice  has  been  found  of  great  benefit  as  a  prophylactic  in 
the  treatment  of  scurvy,  but  this  is  not  due  to  the  citric  acid,  but  to  some 
unknown  substance  in  the  fruit  juices.  Citric  acid  has  been  used  in  rheumatic 
affections,  without  any  marked  improvement  being  elicited  according  to  the 
best  observers. 

XLVII.     CALCIUM. 

The  salts  of  lime  are  present  in  very  large  amount  in  the  tissues  of 
animals,  and  considerable  interest   attaches  to  their  al»sor])tion,  excre- 


CALCIUM  557 

tion,  and  j>oiieriil  action.  They  fonn  the  ^reat  mass  of  t.lie  inor<;anic 
constituents  of  the  bones  and  teeth  of  the  vertebrates  and  of  the  shells 
of  the  invertebrates.  In  addition  it  has  l)een  shown  of  recent  years 
tliat  they  are  present  to  a  considerable  amount  in  the  soft  tissues  and 
are,  in  fact,  essential  to  most  forms  of  living  matter,  and  to  the  activity 
of  certain  ferments. 

Calcium  and  the  other  alkaline  earths  differ  from  the  alkalies  in 
possessing  comparatively  few  very  soluble  salts,  and  they  seldom  effect 
such  changes  in  the  ])hysical  properties  of  the  fluids  of  the  body  as 
have  been  described  under  salt-action  and  chloride  of  sodium.  Even 
the  soluble  salts  penetrate  with  greater  difficulty  into  the  various 
tissues  of  the  body,  which  seem  to  have  much  less  affinity  for  them 
than  for  the  salts  of  the  alkalies.  They  precipitate  colloids,  such  as 
the  proteins,  in  much  more  dilute  solutions  than  the  salts  of  the  alkalies, 
and  the  precipitate  is  not  redissolved  by  dilution  with  water.  This 
precipitation  of  proteins  appears  to  account  for  the  pain  and  irritation, 
which  follow  the  subcutaneous  injection  of  the  more  readily  dissocial)le 
salts  such  as  the  chloride. 

Action. — The  soluble  lime  salts  are  Absorbed  with  great  difficulty 
from  the  stomach  and  intestine  and  retard  considerably  the  absorption 
of  fluid.  They  would  presumably  have  a  cathartic  action  were  they 
not  thrown  out  of  solution  very  readily  by  the  alkaline  fluids.  In 
addition  calcium  forms  insoluble  salts  with  all  of  the  cathartic  acid 
ions,  so  that  no  such  double  effect  can  be  obtained  as  is  seen  from 
magnesium  sulphate.  (See  Saline  Cathartics,  page  101.)  The  greater 
proportion  of  the  lime  taken  either  in  the  food  or  as  a  remedy,  unques- 
tionably leaves  the  body  in  the  stools  entirely  unabsorbed,  while  a 
smaller  quantity  of  it  is  taken  up  from  the  alimentary  canal  whether 
the  lime  be  administered  in  a  soluble  or  in  an  insoluble  form.  This 
circulates  in  the  blood,  chiefly  as  diffusible  salts  (bicarbonate)  but  partly 
in  coml)ination  with  proteins,  and  is  slowly  excreted,  unless  there  is  a 
deficiency  in  the  supply  of  lime,  when  it  may  be  utilized  by  the  tissues. 
When  larger  quantities  are  thrown  into  the  blood  by  intravenous  or 
hypodermic  injection,  the  calcium  of  the  blood  remains  abnormally 
high  for  some  time,  but  all  the  calcium  thus  injected  is  not  in  the  cir- 
culation throughout  its  stay  in  the  body.  Some  of  it  is  temporarily 
deposited  in  some  unknown  organ,  and  is  gradually  withdrawn  and 
excreted  after  the  first  excess  is  eliminated. 

The  lime  is  Excreted  in  part  in  the  urine,  but  for  the  most  part  through 
the  epithelium  of  the  large  intestine.  The  relative  amounts  excreted 
by  the  kidney  and  bowel  seem  to  be  determined  by  the  quantity  of 
available  phosphates  among  other  factors;  if  these  are  present  in  large 
quantities  in  the  blood,  the  calcium  is  excreted  mainly  in  the  bowel  in 
the  form  of  calcium  phosi)hate.  Excess  of  chlorides  in  the  l)ody  fluids 
has  the  opposite  eft'ect,  more  calcium  appearing  in  the  urine.  The 
elimination  of  calcium  thus  appears  to  vary  with  the  character  of  the 
combinations  which  it  can  form ;  if  these  are  soluble  they  appear  in  the 
urine,  while  the  insoluble  ones  tend  to  pass  into  the  stools.     Some  of 


55S  SlliSTAXCES   ACTISC   AFTER   ABSORPTION 

the  <"il(iimi  <>t'  tlir  urine  may  he  in  tlic  form  of  the  (•arl)ainatc  (Al)el  and 
Miiirlicatl).  The  administration  of  ealeium  increases  the  elimination 
of  ma<;nesiiini  in  the  urine,  and  simihirly  magnesium  absorbed  leads  to 
a  larger  excretion  of  calcium  in  the  urine,  while  that  in  the  faces  may  be 
diminished.  Calcium  lessens  the  phosphates  of  the  urine,  and  therefore 
its  acidity,  by  forming  insoluble  phosi)hates  in  the  bowel,  and  thus 
preventing  the  absorption  of  the  phosphates  of  the  food. 

The  calcimn  absorbed  has  no  obvious  effects;  constipation  is  often 
induced  by  lime,  but  it  is  uncertain  whether  this  arises  from  action 
on  the  bowel  neuromuscular  apparatus,  or  is  the  result  of  the  insoluble 
calcium  salts  forming  a  protecti\e  co\ering  over  the  ei)itlielium  and 
thus  lessening  the  reflex  peristalsis  (compare  tannin  group).  Except 
under  special  circumstances,  the  calcium  of  the  food  is  always  suffi- 
cient to  supply  the  needs  of  the  organism,  so  that  lime  salts  given  as 
remedies  have  after  absorption  no  si)ecific  action  due  to  the  calcium, 
but  owe  their  acti^•ity  to  the  anion  exclusi\ely.  Thus,  calcium  l^romide 
may  have  some  effect  if  absorbed,  but  this  effect  is  due  to  the  bromide 
ion",  and  would  be  the  same  if  an  equal  proportion  of  sodium  bromide 
were  taken  up  by  the  blood. 

The  action  of  calcium  on  isolated  organs  is  complicated  by  the  fact  that  it 
must  always  be  applied  along  with  sodium  in  order  to  maintain  the  osmotic 
eciuilibrium,  and  sodium  appears  to  modify  the  lime  action  considerably  as 
will  be  discussed  on  a  later  page.  But  calcium  appears  to  depress  the  neuro- 
nuiscular  connections  in  striated  muscle  like  curara,  and  later  to  weaken  the 
nuiscle  itself.  The  removal  of  lime  is  .said  to  increase  the  irritability  of  the 
terminations  of  the  autonomic  nerves  in  mammals;  on  the  other  hand  the 
vagus  is  stated  to  lose  its  inhibitory  action  on  the  heart  perfused  with  calcium- 
frcc  salt  solution. 

Soluble  calcium  salts  injected  directly  into  the  bloodvessels  seem  to  be 
poisonous,  their  action  resembUng  that  of  digitahs  in  some  respects.  They 
first  accelerate  and  strengthen  the;  heart,  and  in  large  quantities  bring  it  to  a 
standstill,  and  also  have  a  marked  effect  in  contracting  tlie  vessels  when  per- 
fu.sed  through  them.  In  this  way  they  may  sometimes  diminish  the  duiresis 
and  glycosuria  in  animal  experiments.  Large  quantities  injected  intrave- 
nously contract  the  pupil  to  pin-point  size,  apparently  from  action  on  the 
fibres  of  the  sphincter  nuiscle,  for  atropine  has  httle  effect  on  the  myosis. 
Asi)liyxia  causes  dilatation  after  calcium,  liowevcr,  in  the  same  way  as  m  mor- 
l)hine  poisoning.  These  effects  are  absent  when  the  salts  are  taken  up  from 
the  bowel,  mainly  no  doubt  owing  to  their  slow  absorption,  which  prevents 
their  attaining  a  high  concentration  in  the  tissues. 

There  is  some  not  altogether  convincing  evidence  that  lime  salts  lessen 
the  permeability  of  the  cells  of  the  tissues;  for  example,  it  is  statecl  that  in  the 
l)resence  of  traces  of  calcium  dried  cells  take  up  less  water.  This  view  has  been 
further  developed  by  Chiari  and  Januschke,  who  state  that  when  an  annual 
has  been  treated  with  lime  salts  the  intravenous  injection  of  iodides  does  not 
induce  pleural  effusion  and  a'dema,  while  it  has  this  effect  in  untreated  annuals; 
and  similarly,  even  strong  irritants  applied  to  the  conjunctiva  do  not  cause 
marked  swelling  and  etTusion  in  these  treated  animals.  They  attribute  this 
action  to  the  lime  rendering  the  vessel  walls  less  iiermeaMe  by  the  i)lasma;  the 
Rubje(;t  requires  further  investigation. 

Lime  Starvation. — Excess  of  calcinm  in  the  organism  is  therefore 
little  to  be  api)rclicnded  from  the  ordinary  nivthods  of  administration. 


CALCIUM  559 

and  lime  salts  arc  soldoin  used  in  tlicrapeutics  to  induce  changes  in 
the  organism  throu<ili  tlieir  presence  in  excess  in  the  blood,  like  other 
remedies,  such  as  nior])hine  or  stryclniine.  Another  question  arises, 
howe\er,  namely,  whether  the  organism  may  not  be  rendered  abnormal 
by  a  deficiency-  in  the  supply  of  lime,  and  whether  this  deficiency  may 
be*remedied  l)y  the  administration  of  calcium  salts. 

The  efl'ects  of  a  deficiency  of  lime  in  the  food  have  been  the  subject 
of  several  very  careful  in\'estigations,  and  while  the  adult  animal  does 
not  seem  to  sufter  greatly  from  a  very  considerable  reduction  of  the 
calciumof  the  food,  young  growing  animals  develop  marked  abnormal- 
ities, resembling  closely  those  observed  in  rickets  and  osteomalacia  in 
the  human  subject.  In  lime  starvation,  as  in  rickets,  there  is  a  lessened 
deposit  of  lime  in  the  bones,  which  retain  their  cartilaginous  consistency 
and  show  other  deviations  from  the  normal  condition;  in  rickets  the 
bones  alone  are  involved,  while  in  animals  deprived  of  calcium  the  soft 
tissues  also  show  a  lessened  content  of  lime  salts.  Deficiency  of  the 
lime  in  the  food  naturally  affects  young  animals  more  than  adults, 
because  the  former  require  much  more  calcium  to  build  up  the  growing 
skeleton.  But  if  the  lime  of  the  food  is  greatly  reduced  while  a  special 
demand  is  made  on  the  lime  reserve  of  the  body,  the  bones  in  the  adult 
may  also  suffer;  thus  in  pregnant  animals,  in  which  lime  has  to  be 
supplied  for  the  foetal  skeleton,  weakness  of  the  bones  of  the  mother 
simulating  the  osteomalacia  of  human  pregnancy  has  been  observed 
when  the  lime  of  the  food  was  reduced. 

The  effects  of  the  withdrawal  of  lime  have  been  studied  in  some 
Isolated  Organs.  Thus  Ringer  comj^ared  the  ])eha^•io^  of  the  frog's 
heart  when  ])erfused  with  solutions  of  the  salts  of  the  alkalies  with 
that  of  one  perfused  with  the  same  solutions  to  which  minute  traces 
of  lime  were  added,  and  found  that  the  efficiency  of  the  heart  was 
much  increased  and  that  it  survived  very  much  longer  under  the  latter 
conditions;  Locke  has  recently  shown  that  a  similar  relation  exists 
between  the  mammalian  heart  and  the  inorganic  elements  of  serum. 
Lime  salts  exercise  a  similar  effect  in  voluntary  muscle,  which  sur- 
vives much  longer  when  perfused  with  salt  solution  containing  calcium 
than  when  sodium  chloride  solutions  alone  are  used.  Both  the  heart 
and  skeletal  muscle  eventually  cease  to  contract  on  electrical  stimulation 
when  perfused  with  physiological  salt  solution,  but  recover  again  when 
traces  of  lime  salts  are  added  to  it.  hi  the  same  way,  the  irritability 
of  the  frog's  nerve  persists  much  longer  in  salt  solution  containing  a 
lime  salt  than  in  unmixed  salt  solution,  and  may  be  restored  by  the 
addition  of  lime,  when  it  has  disappeared  after  the  prolonged  action 
of  the  0.6  per  cent:  chloride  of  sodium  solution.  Ciliated  epithelium 
continues  to  wave  rhythmically  much  longer  in  lime  solution  than  in 
distilled  water,  in  which  it  swells  up  and  rapidly  loses  its  activity. 
This  probablv'  explains  the  observation  that  some  fish  die  very  soon 
in  distilled  water  but  survive  in  water  in  which  traces  of  lime  are  present. 
Lime  is  also  necessary  for  the  development  of  various  ova;  for  instance, 
frog  spawn  kept  in  water  de\oid  of  lime  salts  fails  to  de^'elop,  or  develops 
abnormally. 


560  SUBSTANCES  ACTING  AFTER  ABSORPTION 

Liiiif  salts  arc  also  indispensable  in  some  processes  wliicli  arc  not 
dependent  on  the  presence  of  living  cells.  Thns  rennet  docs  not 
coagnlatc  milk  except  when  a  lime  salt  is  present,  and  the  Coagulation 
of  the  Blood  may  be  prevented  by  precipitating  its  calcium  salts  in  the 
form  of  oxalates.  Ilammersten  has  recently  shown  that  the  lime  salts 
are  not  necessary  to  the  formation  of  fibrin,  for  this  occnrs  in  oxalate 
solutions  if  fibrin-ferment  be  added  to  fibrinogen.  But  the  fibrin- 
ferment  is  not  formed  except  in  the  presence  of  calcium  salts,  and 
when  oxalates  are  added  to  the  blood  before  this  ferment  is  developed, 
they  prevent  its  formation  and  hinder  clotting.  When  lime  salts  are 
added,  the  ferment  is  liberated  and  coagulation  occurs  at  once.  In 
other  words,  lime  is  not  necessary-  for  the  acti\ity  of  the  fi})rin-ferment, 
but  for  its  development  from  the  prothrombin  or  zymogen,  in  which 
it  exists  in  the  circulating  blood.  Lime  salts  taken  by  the  mouth  do 
not  accelerate  the  clotting  of  blood. 

Other  ferments  act  in  the  absence  of  available  lime  salts.  Thus 
pepsin  digests  when  instead  of  hydrochloric,  oxalic  acid  is  added  to  it, 
but  it  is  unknown  whether  pepsin  is  formed  from  pepsinogen  in  the 
absence  of  lime.  The  trypsinogen  of  the  pancreas  may  be  changed 
to  trypsin  by  lime  salts. 

The  higher  organisms,  both  animals  and  plants,  ha\e  thus  been 
shown  to  require  lime  for  some  of  their  functions,  and  it  is  probably 
necessary  for  many  others  in  which  its  importance  has  not  yet  been 
recognized.  The  lowest  forms  of  life,  however,  includhig  the  bacteria 
and  some  of  the  moulds,  seem  to  be  able  to  live  without  it.  To  induce 
the  effects  of  lime  starvation,  it  is  not  always  necessary  to  withdraw 
lime  from  the  food,  for  they  may  be  caused  by  the  presence  of  any 
substance  which  prevents  the  dissociation  of  tlie  calcium  ion.  Thus, 
oxalate  solutions  added  to  the  blood  or  milk,  or  to  the  nutrient  liuid 
for  perfusion  of  the  heart,  have  the  same  effects  as  the  withdrawal  of 
lime.  Food  containing  large  quantities  of  oxalate  salts  has  in  some 
cases  induced  symptoms  in  animals  resembling  those  of  lime  star\'ation, 
and  it  seems  probable  that  some  of  the  sym])toms  of  fluoride  action 
are  also  explicable  from  their  precii)itating  the  lime  salts  of  the  food 
and  of  the  blood.    (See  Oxalates  and  Fluorides.) 

Balanced  Salt  Solutions. — A  curious  relationship  has  been  shown  to  exist 
between  the  calcium  and  potassium  salts.  Thus  when  a  frog's  henrl  is  i)erfused 
with  sodium  chloride  solution  containing  a  trace  of  calcium,  the  movements 
an;  not  entirely  normal,  the  contraction  being  somewhat  prolonged  and  the 
relaxation  much  retarded.  If  a  trace  of  jjotassium  cliloride  is  addecf,  however, 
the  contraction  becomes  normal  in  character.  On  the  other  hand  the  eii'ect  of 
potassium  on  the  frog's  heart  is  antagonized  by  the  addition  of  lime.  The 
same  holds  tiue  for  voluntary  muscle,  the  salts  of  calcium  tending  to  neutralize 
the  effects  of  potassium,  and  rice  verso,  and  in  s(>veral  other  relations  an 
antagonism  has  been  observed  between  tlu-se  two  metals.  Another  marked 
antagonism  has  nn-ently  been  studied  by  Meltzer,  who  shows  that  toxic  ([uan- 
tities  of  magnesium  can  be  completely  neutralized  by  calcium.  And,  as  the 
symi)toins  of  magnesium  ])oisoning  in  manunals  are  characteristic,  the  recovery 
of  :inimals  when  calciuni  is  inje<-ted  is  very  striking;  magnesium  induces  narcosis 


CALCIUM  561 

iiiul  iuia'.stlu'.si;i,  which  is  iiuincdiately  foiiiilei'actcd  by  calcium,  and  the;  animal 
assumes  its  normal  posture. 

Another  question  that  has  excited  much  interest  recently  is  the  relation 
between  sodium  and  calcium.  It  has  alread}^  been  noted  that  the  frog's  heart 
perfused  witli  sodium  chloride  solution  soon  ceases  to  beat,  but  can  be  restored 
by  the  addition  of  calcium  and  potassium  to  the  circulating  medium.  The 
ordinary  explanation  (Ringer,  Howell)  is  that  the  calcium  and  potassium  are 
necessary  to  the  activity  of  the  heart  and  that  when  pure  salt  solution  is  perfused 
these  elements  diffuse  into  it  and  are  lost  from  the  heart  muscle;  this  diffusion 
is  prevented  ff  calcium  and  potassium  be  contained  in  the  solution,  and  the 
heart,  retaining  the  salts  essential  to  its  activity,  continues  to  beat.  Another 
explanation  has  been  offered  by  Loeb,  who  supposes  that  the  lime  and  potassium 
are  not  directly  essential,  but  that  they  neutralize  the  poisonous  effects  of 
sodium.  This  poisonous  action  of  sodium  has  not  been  generally  recognized, 
but  is  well  shown  by  the  behavior  of  a  small  fish  (fundulus)  living  in  salt  water, 
which  can  be  transferred  to  distilled  water  without  injury,  thus  showing  that 
neither  sodium  nor  calcium  is  necessary  in  its  environment.  But  if  it  be  put 
in  sodium  chloride  solution  of  the  same  strength  as  sea  water,  it  dies,  so  that 
sodium  is  poisonous  to  it  unless  when  antagonized  by  the  other  constituents  of 
sea  water;  the  essential  elements  are  calcium  and  potassium,  for  wdien  these  are 
added  to  the  injurious  sodium  solution,  the  fish  lives  as  well  as  in  sea  water. 
This  series  of  experiments  certainly  forms  a  strong  support  for  Loeb's  theory 
that  calcium  is  not  directly  essential  to  rhythmic  movement,  but  only  neutralizes 
the  effects  of  sodium.  On  the  other  hand,  the  calcium  salts  themselves  are 
poisonous  when  they  are  not  counterbalanced  by  sodium  and  potassium;  in  this, 
as  in  many  other  instances,  there  must  be  maintained  between  the  inorganic 
constituents  of  the  surrounding  fluid  an  equilibrium,  such  as  exists  in  sea  water 
in  the  case  of  the  fundulus,  and  in  the  blood  plasma  in  the  case  of  the  heart  and 
other  organs. 

The  salts  of  the  alkaline  earths  are  said  to  inhibit  the  hsemolytic  action  of 
certain  serums,  while  those  of  the  alkalies  have  not  this  effect  when  applied  in 
the  same  concentration;  this  may  perhaps  be  connected  with  the  tendencj^  the 
former  have  to  coagulate  proteins.  The  formation  of  protein  combinations  is 
apparently  the  explanation  of  the  disappearance  of  lime  salts  when  they  are 
perfused  through  organs  or  when  pieces  of  tissue  are  soaked  in  them.  Cartilage 
seems  to  combine  more  readily  with  hme  than  the  other  tissues. 

Therapeutic  Uses. — Calcium  salts  are  used  in  medicine  for  a  number 
of  different  purposes;  thus  the  alkaline  preparations  may  be  pre- 
scribed to  lessen  the  acidity  of  the  stomach,  and  the  oxide  may  be 
employed  as  a  caustic.  But  these  owe  their  use,  not  to  the  calcium 
ion,  but  to  the  other  part  of  the  molecule — the  anion.  As  a  matter 
of  fact,  calcium  has  few  important  effects  of  its  own  and  is  seldom 
prescribed  for  any  action  which  it  might  have  on  the  living  tissues. 
The  question  has  been  raised,  however,  whether  calcium  may  not  be 
given  therapeutically  to  supply  a  deficiency  of  lime  in  the  body.  The 
particular  conditions  which  have  been  treated  on  this  theory  are 
rickets  and  osteomalacia,  m  both  of  which  there  is  unquestionably  too 
little  lime  in  the  bones,  and  the  treatment  has  been  thought  to  be 
rational,  because  symptoms  similar  to  those  of  rickets  have  been 
induced  in  young  animals  whose  food  contained  too  small  a  proportion 
of  lime.  In  the  case  of  rickets  and  osteomalacia,  however,  there  is 
no  reason  to  suppose  that  the  food  is  deficient  in  calcium;  in  fact, 
children  are  said  to  be  more  liable  to  rickets  when  fed  on  cows'  milk 
36 


562  SCHSTAXCES   ACT  ISC   AFTER   ABSORPTION 

tliiiii  when  iiursod  hy  the  motlK-r,  although  the  milk  of  tlit'  cow  con- 
tains more  lime.  On  the  other  liaiul,  ])atient.s  suffering  from  rickets 
absorb  h'me  and  excrete  it  again  in  exactly  the  same  way  as  normal 
persons,  and  although  their  bones  contain  unusually  small  amoinits  of 
lime,  the  other  tissues  contain  rather  more,  or,  at  any  rate,  not  less 
than  normal.  Rickets  is  not  due  to  a  lack  of  lime  in  the  food,  there- 
fore, nor  in  fact  in  the  tissues  generally,  but  to  some  abnormal  con- 
dition which  ])revents  the  lime  salts  from  being  deposited  in  the 
bones,  although  they  are  ])resent  in  abundance  in  the  blood.  In  cases 
of  lime  starvation  similar  symptoms  may  appear,  })ut  here  the  cause 
is  the  want  of  lime,  which  is  not  presented  in  sufficient  quantities, 
although  the  bone-forming  cells  are  ready  to  deposit  it.  In  this  case 
the  other  tissues  are  also  deficient  in  calcium  as  well  as  the  bone. 
From  these  considerations  it  follows  that  lime  salts  are  not  likely  to 
be  of  benefit  in  rickets  (and  the  same  holds  true  for  osteomalacia), 
unless  when  it  is  due  to  lime  starvation,  a  condition  which  is  unlikely 
to  arise  in  the  human  subject.  Experience  has  demonstrated  also  that 
the  lime  salts  are  quite  incapable  of  impro\'ing  either  osteomalacia  or 
rickets. 

It  has  also  been  proj)osed  to  treat  with  lime  cases  in  which  the  blood 
seemed  less  capable  of  clotting  than  normally — particularly  hjemo- 
})hilia,  and  the  treatment  has  been  extended  to  aneurism,  hcnemoptysis, 
and  gastric  and  intestinal  haemorrhage.  In  ha-mophilia  there  is  no 
deficiency  of  lime  in  the  blood,  however,  and  still  less  is  this  the  case 
in  aneurism  and  ha?morrbage.  And  the  admhiistration  of  lime  by 
the  mouth  does  not  accelerate  or  in  any  way  alter  the  clotting  of  blood. 
Finally  no  distinct  clinical  results  have  been  obtained  by  careful  ob- 
servers, and  the  treatment  may  be  dismissed  as  erroneous.  A  still 
further  de\elopnient  of  the  theory  has  led  to  the  use  of  calcium  in  the 
most  diverse  conditionr,  in  which  it  was  suggested  that  the  symptoms 
arose  from  excessive  transudation  of  lymph  into  the  tissues;  and  the 
clinical  results  are  equally  disappointing. 

jMacCallum  has  recently  stated  that  in  dogs  from  whom  the  i)ara- 
thyroid  glands  IvAXii  been  removed,  the  lime  contents  of  the  brain  and 
blood  ma>'  be  very  much  diminished,  and  that  the  symptoms  of  tetany 
which  arise  after  the  oj^eration  may  be  relieved  by  lime  salts  gi^•en 
intravenously  or  by  the  mouth.  A  few  cases  of  tetany  in  man  also 
imi)ro\c(l  under  treatment  with  calcium  salts. 

Prepakationh. 

Calcii  Chlorldum  (U.  S.  P.,  R.  P.)  (CaClo),  a  white  salt  with  a  sliarp,  saline 
taste,  very  dolifjuosccnt  and  soluble  in  water.    0.5  G.  (7^  grs.);  B.  P.,  5-15  grs. 

Calcii  Laclas  (H.  P.)  (Ca(C'3H503),',5II..O),  a  wliito.  almost  tasteless  powder, 
soluble  in  1S.5  ])arls  of  water.     0.6-2  C.  (10-30  grs.) 

Calcium  chloride  is  the  salt  which  gives  the  least  conii)lica(e(l  calcium  action, 
and  is  c(Mis('(iu('iitly  seldom  used,  Ix'cause,  as  has  been  ex])lainc(l,  the  calcium 
ion  is  of  conii)aratively  little  sei'vice  in  therapeutics.  It  has  a  strong  attraction 
for  water  and  is  readily  dissociable  and  is  therefore  more  initant  than  the  other 
chlorides  of  the  alkalies  and  alkaline  earths,  and  ouiiht  to  l>c  prcsciihcil  only  in 


I 


CALCIUM  503 

dilute  solution.  It  is  absorbed  with  great  difficulty,  and  has  l)eou  suggested  in 
the  treatment  of  sonic  forms  of  dyspepsia  and  in  ha'morrliage.  Instead  of  the 
chloride,  tlie  lactate  has  been  employed  in  the  same  doses  and  has  the  ad\antage 
of  dissociating  more  slowl}^  and  thus  causing  less  pain  and  irritation  when  it  is 
injected. 

Calx  (U.  S.  P.,  B.  P.)  (CaO),  unslaked  lime,  is  a  corrosive  and  disinfectant, 
and  is  clianged  at  once  to  the  hydrate  in  the  presence  of  water.  It  differs  from 
the  caustic  alkalies  in  the  insolubility  of  its  hydrate,  which  therefore  fails  to 
penetrate  deeply  and  does  not  spread  so  widely  as  potassium  and  sodium 
hydrates.  It  is  seldom  employed  alone  as  a  corrosive,  but  mixed  with  potassium 
hydrate  as  Vienna  paste  [Potassa  cum  Calce,  U.  S.  P.)  has  had  some  popu- 
larity. 

It  is  used  as  a  disinfectant  where  large  quantities  of  organic  matter  have  to 
be  rendered  harmless,  as  in  epidemics,  on  battle  fields,  and  in  the  dejections 
of  large  hospitals.  It  ought  to  be  mixed  with  the  matter  to  be  disinfected  as 
thoroughly  as  possible.  Lime  possesses  the  advantage  over  other  disinfectants 
of  being  cheap  and  easily  procurable  in  large  quantities. 

Calcii  Hydras  (B.  P.),  slaked  lime  (Ca(H0)2),  may  also  be  used  as  a  dis- 
infectant. 

Liquor  Calcis  (U.  S.  P.,  B.  P.),  lime  water,  is  a  saturated  solution  of  calcium 
hydrate  or  slaked  lime  and  contains  about  0.1-0.17  per  cent.  It  is  a  clear  fluid 
with  a  saline  and  feebly  caustic  taste.     16  c.c.  (4  fl.  drs.);  B.  P.,  1-4  fl.  oz. 

Syrupus  Calcis  (U.  S.  P.),  Liquor  Calcis  Saccharatus  (B.  P.),  syrup 
of  lime,  contains  calcium  hydrate  kept  in  solution  in  water  by  sugar,  with 
which  it  is  probably  combined  chemicallJ^    2  c.c.  (30  mins.);  B.  P.,  15-60  mins. 

LiNLMENTUM  Calcis  (LT.  S.  P.,  B.  P.),  lime  liniment,  or  Carron  oil,  contains 
equal  parts  of  lime  water  and  olive  or  linseed  oil. 

The  preparations  of  the  oxide  and  hydrate  owe  tJieir  activity  chiefl}^ 
to  their  alkalinity  and  not  to  the  calcinm,  but  differ  from  the  hydrates 
of  the  alkalies  in  their  insolubility  and  in  their  slow  alxsorption.  Lime 
water  and  the  syrup  are  slightly  caustic,  more  especially  the  latter 
and  tend  to  neutralize  the  gastric  juice.  They  have  an  astringent 
effect  in  the  intestine  which  has  not  yet  been  explained,  but  is  probably 
due  to  their  forming  an  insoluble  compound  with  the  surface  proteins, 
in  the  same  way  as  tannic  acid,  or  to  their  being  deposited  as  the 
carbonate  or  phosphate  and  thus  protecting  the  epithelium  from  irrita- 
tion. Lime  water  is  used  in  some  dyspeptic  conditions,  especially  in 
vomiting.  It  is  often  added  to  milk  in  intestinal  irritation  in  children 
and  in  ty])hoid  fever,  as  it  is  found  that  milk  thus  treated  coagulates 
in  finer  particles  than  when  given  alone,  and  is  better  digested  and  less 
liable  to  disturb  the  intestine.  Lime  water  or  syrup  of  lime  is  also 
used  as  an  intestinal  astringent  in  diarrhoea,  especially  in  children. 
As  an  antacid  in  the  stomach,  lime  is  inferior  to  magnesia  and  other 
alkalies,  because  it  tends  to  delay  the  evacuation  of  the  contents.  Lime 
water  has  been  used  in  rickets,  which  seems  singularly  irrational,  for 
cows'  milk  contains  a  somewhat  higher  percentage  of  lime.  It  has 
also  been  sprayed  against  the  false  membrane  of  diphtheria,  which 
it  is  said  to  dissolve.  Lime  water  is  not  applicable  in  cases  of  acid 
poisoning,  as  it  contains  much  too  little  of  the  base  to  be  serviceable, 
but  the  syrup  may  be  used,  or  lime  shaken  up  with  water  (milk  of 
lime).  The  treatment  with  lime  is  specially  indicated  in  cases  of  oxalate 
poisoning. 


564  SUBSTANCES  ACTING  AFTER  ABSORPTION 

Lime  water  has  been  used  externally  as  a  proteetive,  mildly  astrin- 
gent applieation  to  ulcers,  and  the  lime  liniment  has  been  largely  used 
in  the  treatment  of  burns.  It  derives  its  name  of  Carron  oil  from 
ha^■ing  been  used  for  this  purj)ose  in  the  iron  works  at  Carron. 

Creta  Prccparata  (U.  S.  P.,  B.  P.),  prepared  chalk,  chalk  ])urificd  by  washing 
and  suspension  in  water  (CaCOs).    1  G.  (15  grs.) ;  B.  P.,  15-00  grs. 

PuLVis  CRETiE  CoMPOSiTus  (U.  S.  P.),  a  mixturc  of  prepared  chalk,  sugar 
and  acacia.     2  G.  (30  grs.). 

PuLVis  C'RET.^i  Aromaticus  (B.  P.),  aromatic  chalk  powder,  contains  chalk 
along  with  sugar  and  a  number  of  carminatives  belonging  to  the  group  of 
volatile  oils.    10-60  grs. 

PuLvis  Cret^  Aromaticus  Cum  Opio  (B.  P.)  is  a  mixturc  of  39  parts  of 
the  aromatic  powder  with  one  of  opium,  and  therefore  contains  2^  per  cent, 
of  opium.     10-40  grs. 

MiSTURA  Cretjb  (U.  S.  p.),  chalk  mixture,  is  chalk  suspended  in  cinnamon 
water  by  means  of  gums.     16  c.c.  (^  fl.  oz.). 

The  preparations  of  the  carbonate  of  lime  are  used  as  antacids  in 
hyperacidity  of  the  stomach,  especially  when  this  is  coml)ined  with  a 
tendency  to  diarrhoea.  The  mixture,  or  the  aromatic  powder  B.  P., 
is  the  form  generally  used,  and  may  be  prescribed  with  opium  or  with 
other  astringents.    Chalk  has  also  been  used  in  rickets. 

■Externally,  })repared  chalk  is  used  as  a  powder  to  protect  irritated 
parts  of  the  skin  and  occasionally  in  ulceration;  it  is  the  chief  ingredient 
in  most  tooth  powders.  In  older  treatises  on  therapeutics  great  virtues 
are  ascribed  to  various  natural  objects  which  are  composed  for  the 
main  part  of  chalk  or  other  salts  of  lime,  and  among  which  burned 
bones,  coral,  coralline  and  cuttlefish  bone  may  be  mentioned. 


Bibliography. 

See  Oxalates  and  Sodium  Chloride. 

Jankau.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxix,  p.  237. 

Raudnilz.     Ibid.,  xxxi,  p.  343. 

Abel  u.  Muirhead.     Ibid.,  xxxi,  p.  15. 

Radel.     Ibid.,  xxxiii,  pp.  79,  90. 

Rey.     Ibid.,  xxxv,  p.  295.    Deutsch.  nied.  Woch.,  1895,  p.  569. 

Ringer.     Journ.  of  Physiol.,  iii-xvi. 

Howell  (and  his  pupils).  Ibid.,  xiv,  p.  198;  xvi,  p.  476.  Aiiicr.  Jnurn.  of  I'hjs.,  v, 
p.  338;    vi,  p.  181. 

Loeb,  Lingle,  Lillie,  Moore.  Amer.  Journ.  of  Phys.,  iv,  p.  265;  v,  pp.  56,  87,  362 
vi,  p.  411. 

Kitasato.     Zts.  f.  Hygiene,  iii,  p.  404. 

Pfuhl.     Ibid.,  vi,  p.  97. 

Binel.     Comptes  rcndus  d.  I'Acad.  de  Science,  cxv,  p.  251. 

Hammarstcn.     Ztschr.  f.  phys.  Chem.,  xxii,  p.  333. 

Strauss.     Ztschr.  f.  klin.  Med.,  xxxi,  p.  493. 

Miwa  u.  Stoellzner.     Zionler's  licit riisc  zu  Path.,  xxiv,  p.  578. 

Mellzcr  and  Auer.     See  Magnesium  bibliography. 

Addis.     Quart.  .Tourn.  of  Med.,  ii. 

MacCallum  and  Voegtlin.     Trans.  Assoc.  Amer.  Phys.,  1908,  p.  416. 

Chiari  u.  Januschkc.     Arch.  f.  exp.  Path.,  Ixv,  p.  120. 

Mendel  and  Benedict.     Amer.  Journ.  of  Physiol.,  xxv,  p.  23. 


OXALATES  AND  FLUORIDES  505 


XLVm.    OXALATES    AND    FLUORmES. 

The  oxalates  (NaOOC — COONa)  and  the  fluorides  owe  the  greater  part  of 
then-  action  to  their  power  of  precipitating  the  calcium  of  the  tissues,  though 
they  may  also  cause  other  effects;  this  precipitation  renders  them  poisonous 
to  most  forms  of  living  matter,  of  which  lime  is  generally  an  essential  constituent. 
The  oxalate  action  may  be  removed  in  many  instances  by  adding  lime  salts 
in  excess. 

In  the  frog  they  cause  depression  and  final  paralysis  of  the  central  nervous 
system,  and  later  of  the  terminations  of  the  peripheral  nerves  and  the  muscles 
and  heart;  twitching  and  fibrillary  contractions  of  the  voluntary  muscles  are 
often  observed  first. 

In  mammals  there  is  apparently  at  first  a  stimulation  of  the  medullary 
centres,  for  rapid,  deep  breathing  occurs  in  the  rabbit,  and  vomiting  and  nausea 
in  the  dog,  and  according  to  some  observers,  the  arterial  tension  is  first  increased 
through  stimulation  of  the  vasomotor  centre.  Later  the  movements  are  wanting 
in  coordination,  the  respiration  becomes  slow  and  dyspnoeic,  the  heart  is  weak, 
and  the  animal  becomes  comatose  and  dies,  sometimes  in  convulsions. 

In  cases  of  oxalate  poisoning  in  man,  the  early  s.ymptoms  are  great  mus- 
cular weakness,  twitching  of  the  muscles,  especially  of  those  of  the  face,  more 
rarely  convulsions;  later  there  follows  collapse  with  a  weak,  fluttering  pulse, 
pallor  or  cyanosis,  coma  and  death. 

Oxalates  are  very  poisonous  to  all  forms  of  animal  life  and  to  plants  con- 
taining chlorophyll,  but  are  harmless  to  the  moulds,  bacteria  and  some  algae. 
The  fluorides  are  equally  poisonous  to  the  higher  organisms,  and  in  addition 
have  considerable  antiseptic  power,  one  part  in  200  of  water  being  sufl^icient 
to  arrest  the  growth  of  bacteria.  Both  are  absorbed  with  great  diflficulty  from 
the  stomach  and  intestine,  and  cause  irritation  and  effusion  of  liquid  except 
in  very  dilute  solutions.  Added  to  the  blood  outside  or  inside  the  body,  they 
prevent  its  coagulation,  and  the  remiet  ferment  also  fails  to  coagulate  milk  in 
the  presence  of  small  quantities  of  oxalate.  The  frog's  heart  is  very  much 
weakened  by  the  addition  of  oxalate  of  sodium  to  the  blood  perfused  through  it, 
while  the  mammalian  heart  is  not  affected  by  very  small  quantities,  l^ut  if  the 
injection  of  oxalate  be  continued,  becomes  suddenly  weaker.  According  to 
some  observers,  the  terminations  of  the  autonomic  nerves  are  rendered  more 
excitable  under  oxalates,  and  this  manifests  itself  in  salivation,  ready  dilation 
of  the  pupil,  variations  in  the  rate  of  the  heart,  and  in  an  abnormal  sensitiveness 
to  adrenaline  and  pilocarpine  (Chiari  and  Frohlich). 

When  the  ordinary  nerve-muscle  preparation  is  soaked  in  oxalate  or  fluoride 
solution,  the  same  twitching  and  tremor  of  the  muscle  is  observed  as  when  the 
salt  is  injected  into  the  frog.  Later  the  nerve  ends  are  paralyzed,  and  the  nerve 
fibres  lose  their  irritability,  as  is  indicated  by  the  disappearance  of  the  electrical 
current  of  action.  The  fluorides  are  powerful  local  irritants,  small  quantities 
applied  to  the  conjunctiva  causing  congestion  and  mflammation.  Both  fluorides 
and  oxalates  irritate  the  stomach  and  induce  nausea  and  vomiting. 

The  fluorides  absorbed  from  the  alimentary  canal  are  excreted  by  the  urine, 
but  this  takes  place  very  slowly,  and  much  of  the  fluoride  is  stored  up  in  the 
body,  some  in  the  liver  and  skin,  but  most  in  the  bones  in  the  form  of  calcium 
fluoride.  Crystals  of  this  very  insoluble  salt  are  found  in  masses  in  the  Haver- 
sian canals,  and  increase  the  hardness  and  brittleness  of  the  bones. 

Practically  the  whole  of  the  oxalate  ingested  is  excreted  in  the  urine  in  the 
form  of  oxalate  of  calcium,  and  the  insoluble  crystals  are  often  deposited  along 
the  urinary  tubules  and  may  stop  them  up  entirely  and  thus  cause  anuria,  con- 
gestion, and  inflammation  of  the  kidney;  albuminuria  is  often  the  most  marked 
symptom  in  slight  poisoning  in  man.  The  deposits  of  oxalates  often  form  white 
lines  running  from  the  base  to  the  apex  of  the  renal  pyramids,  which  are  fjuite 
evident  macroscopically  at  the  autopsy.  SmJxll  oxalate  calculi  have  also  been 
produced  in  the  pelvis  of  the  kidney,  bladder,  or  ureter  through  the  prolonged 


566  SUBSTANCES  ACTIXa  AFTER  ABSORPTION 

adininistralioii  of  oxalate  to  animals.  Not  infrequently  these  renal  changes  are 
tho  only  lesions  found  post-mortem  in  cases  of  poisonino;  with  oxalates. 

The  i)n)lon<!;c(l  administration  of  oxalates  to  animals  has  been  found  to  induce 
changes  in  tlie  skeleton  identical  with  those  arising  from  lime  starvation;  for 
example,  sheep  fed  on  plants  containing  much  oxalate  are  found  to  have  less 
lime  in  the  bones  than  usual. 

The  other  members  of  the  oxalate  series,  malonates  (CH2(COONa)2)  and 
succinates  (  (CH2)2(COONa)2),  differ  from  the  oxalates  in  being  very  much 
less  poisonous,  the  fatal  dose  of  malonate  of  soda  l)eing  about  twenty  times 
that  of  the  oxalate,  and  the  succinate  being  almost  indifferent.  The  malonate 
is  almost  comjiletely  oxidized  in  the  tissues,  and  succinate  disappears  com- 
pletely. It  is  significant  that  malonic  and  succinic  acids  form  much  more 
soluble  salts  with  lime  than  does  oxalic  acid.  Both  malonate  and  succinate  of 
sodium  are  absorbed  only  slowly  from  the  intestine,  and  act  as  saline  cathartics. 

Hydrofluoric  acid  is  an  exceedingly  powerful  caustic,  destroying  the  nmcous 
membranes  wherever  it  comes  in  contact  with  them.  It  has  been  observed  that 
workers  in  certain  departments  of  glass  factories,  in  which  the  atmosphere 
contains  a  small  amount  of  this  acid,  are  very  seldom  attacked  by  tuber- 
culosis, and  an  attempt  has  been  made  to  treat  pulmonarj^  phthisis  by  the 
inhalation  of  very  dilute  vapors.  The  results  have  not  been  successful,  although 
there  is  no  question  that  hydrofluoric  acid  is  a  powerful  germicide. 

Sodium  fluorosilicate  (SiFlNa2)  has  also  been  used  as  an  antiseptic  in  solution. 
It  has  been  found  to  cause  nausea,  eructation,  and  slowness  of  the  pulse  when 
swallowed. 

The  oxalates  are  not  used  in  therapeutics.  In  cases  of  oxalate  poisoning 
the  natural  antidote  is  lime,  which  forms  an  insoluble  precipitate  in  the  stomach 
and  may  also  relieve  the  symptoms  induced  by  the  withdrawal  of  lime  from 
its  normal  combination  in  the  tissues.  At  the  same  time  large  quantities  of 
water  and  diuretics  may  be  given  in  order  to  wash  out  the  crystals  of  oxalate 
from  the  urinary  tuljules. 

Bibliography. 
Oxalates. 

(Soe  (lalcium.) 

Krohl.     Arb.  a.  d.  pharm.  Inst,  zu  Dorpat,  vii,  p.  1.30. 

Neuherger.     Archiv.  f.  exp.  Path.  u.  Pharin.,  xxvii,  p.  .39. 

Pohl.     Ibid.,  xxxvii,  p.  413. 

Ebstein  u.  Nicolaier.     Virchow's  Arch.,  cxlviii,  p.  36G. 

Ringer.     Practitioner,  xxxiv,  1885,  p.  81. 

Locke.     Journ.  of  Phys.,  xv,  p.  119;   xvii,  p.  293. 

Howell.     Ibid.,  xvi,  p.  476. 

Heymanns.     Arch.  f.  Anat.  u.  Phys.,  1889,  p.  168. 

Vietinglioff-Scheel.     Arch,  internat.  dc  pharmacodyn.,  viii,  p.  225. 

Chiari  and  Frohlich.     Arch.  f.  exp.  Path.,  Ixvi,  p.  110. 

Gros.     Arch.  f.  exp.  Path.,  Ixxi,  p.  397. 

Fluorides. 

Tappclncr.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxv,  p.  203;    xx\ii,  p.  108. 

Schulz.     Ibid.,  xxv,  p.  326. 

Hewelke.     Deutsch.  mod.  Woch.,  1890,  p.  477. 

Langgaard.     Tlicrap.  Monatsch.,  1888,  p.  178. 

Gotlbrecht.     Ibid.,  1889,  p.  411. 

Siegfrkd.     Arch,  internat.  de  Pharmacodyn.,  ix,  p.  225. 

XLIX.    BARIUM,   STRONTIUM,  AND  MAGNESIUM. 

Barium  is  the  most  {joisonous  of  the  alkaline  earths,  but  reseml)les  the  others 
ill  ju'iictiating  with  difliculty  into  the  epithelium  of  the  alimentary  canal,  and 
is  therefore  alhsorbed  very  slowly.  It  has  a  characteristic  action  on  many 
forms  of  muscular  tissue,  resembling  closely  that  of  veratrine,  and  the  con- 
ti'aclioii  of  llic  frog's  muscle  under  barium  is  thus  stronger  than  uonually,  and 


BARIUM,  STRONTIUM,  AND  MAGNESIUM  567 

is  very  greatly  prolonged;  this  action  is  not  opposed  by  curara  and  is  therefore 
believed  to  be  exerted  on  the  contractile  siil)stance  directly.  The  frog's  heart 
beats  more  strongly,  but  more  slowly  from  a  similar  action  on  the  muscle  fibres, 
and  the  walls  of  the  stomach  and  intestine  are  thrown  into  violent  contraction 
fi-om  the  action  of  the  metal  on  the  unstriated  muscle  fiijre.  Tlusre  is  some 
question  as  to  whether  the  central  nervous  system  is  acted  on  in  the  frog,  but 
in  the  mannnal  barium  salts  injected  intravenously  cause  violent  tonic  and 
clonic  spasms,  from  their  stimulating  the  spinal  cord  and  medulla  oblongata. 
The  action  on  the  alimentary  canal  induces  vomiting  and  purging  with  very 
active  peristalsis.  The  heart  is  accelerated  and  the  blood-pressure  is  enormously 
increased  at  first,  and  then  undergoes  slow  undulations  for  some  time.  The 
increased  tension  may  be  due  to  the  cardiac  action  in  part,  but  is  chiefly  to  be 
ascribed  to  a  very  marked  contraction  of  the  muscular  walls  of  the  vessels. 
The  frog's  heart  eventually  assumes  an  irregular  peristaltic  form  of  contraction 
and  ceases  in  systole,  as  in  digitalis  poisoning,  and  the  changes  in  the  mammalian 
heart  also  resemble  those  caused  by  this  series.  Barium  in  sufficient  quantities 
finally  paralyzes  the  central  nervous  system.  In  fatal  poisoning  in  animals 
haemorrhages  have  been  found  in  the  stomach,  intestine,  kidney,  and  other 
organs. 

Barium  is  quite  incapable  of  replacing  calcium  in  its  relations  to  living  matter, 
and  accordingly  chloride  of  sodium  solutions  to  which  barium  chloride  has  been 
added  do  not  tend  to  keep  the  frog's  heart  active  as  do  those  containing  lime. 
Some  authors  hold  that  barium  can  replace  calcium  to  an  imperfect  degree  in 
the  coagulation  of  the  blood,  but  this  is  denied  by  others.  Potassium  salts 
tend  to  neutralize  the  effect  of  barium  on  the  heart  and  muscles,  the  relation 
resembling  that  which  they  bear  to  lime. 

Barium  is  absorbed  slowly  from  the  intestine  and  is  found  to  be  stored  in 
the  bones  to  some  extent,  and  to  be  excreted  by  the  intestinal  epithelium,  only 
traces  appearing  in  the  urine. 

It  has  been  suggested  as  a  substitute  for  digitalis,  but  has  seldom  been  used 
in  practical  therapeutics.  In  veterinary  practice  it  is  often  employed  as  a 
purgative. 

Strontium  is  a  comparatively  inert  substance  even  when  injected  directly 
into  the  blood,  resembling  calcium  in  its  action  in  the  body  as  far  as  is  known, 
but  being  even  less  poisonous.  It  contracts  the  muscles  somewhat,  tends  to 
lessen  the  dilatation  of  the  heart,  and  prolongs  the  contraction  of  muscle,  though 
only  to  a  slight  extent.  It  has  not  the  antagonistic  effects  to  magnesium  which 
are  possessed  by  calcium,  nor,  on  the  other  hand,  does  the  last  named  prevent 
the  symptoms  induced  by  large  quantities  of  strontium.  It  is  absorbed  very 
slowly  from  the  intestine  like  the  other  alkahne  earths,  and  is  depositecl  in 
small  quantities  in  the  bones  of  growing  animals,  especially  when  there  is  a 
deficiency  of  lime  in  the  food;  but  it  cannot  be  used  to  replace  the  calcium 
of  the  food,  animals  treated  thus  showing  the  symptoms  of  lime  starvation.  It 
is  excreted  in  small  quantities  by  the  urine,  but  mainly  by  the  bowel.  Strontium 
salts  have  been  used  to  a  limited  extent  in  therapeutics,  not  for  the  effect  of 
the  strontium  ion,  but  for  the  bromide,  iodide  or  salicylate  effects  of  its  salts. 
In  view  of  the  fact  that  the  strontium  salts  are  more  slowly  absorbed  than  the 
corresponding  ones  of  sodium  and  potassium,  there  would  seem  to  be  good 
grounds  for  al)andoning  their  use. 

The  Magnesium  Salts  have  recently  been  shown  by  Meltzer  to  have  a  very 
powerful  action  when  injected  hypodermically  or  intravenously.  The  most 
characteristic  effect  is  complete  ansesthesia,  resembling  that  induced  by  the 
chloroform  group,  and  ending  in  fatal  cases  in  paralysis  of  the  respiratory 
centre.  This  arises  from  direct  affection  of  the  central  nervous  system,  and 
immediate  recovery  follows  the  injection  of  a  calcium  salt,  which  opposes  the 
magnesium  action  in  the  same  way  as  it  does  that  of  pure  sodium  (see  Cal- 
cium). Ajiplied  to  a  nerve  trunk,  magnesium  salts  in  25  per  cent,  solution 
act  in  the  same  way  as  cocaine,     paralyzing  first  the  afferent  and  later  the 


508  SUBSTANCES  ACTING  AFTER  ABSORPTION 

efferent  fibres,  and  injected  into  the  intradural  space  they  cause  complete 
anresthesia  of  the  lower  part  of  the  body  like  cocaine;  magnesium  sulphate 
has,  in  fact,  been  substituted  for  cocaine  occasionally  for  surgical  operations 
and  in  the  treatment  of  tetanus.  The  ana-sthesia  lasts  very  much  longer  and 
this  rcMiders  it  unsuitable  for  surgical  work,  but  several  cases  of  tetanus  treated 
bv  sul)dural  injection  of  magnesium  sulphate  have  recovered.  (Dose,  about 
0.02  G.  per  kg.  in  man.)  The  same  anaesthetizing  action  is  seen  in  the  lower 
invertebrates  when  a  magnesium  salt  is  added  to  the  water  in  which  they  live. 
Magnesium  has  comparatively  little  effect  on  the  heart,  tending  to  lessen  the 
excitability  of  the  vagus,  and  this  effect  may  also  be  aboli.shed  by  hme  salts. 
It  reduces  the  irritability  of  the  intestine  when  injected  intravenously  and 
arrests  the  peristalsis  aroused  by  physostigmine  or  barium.  It  also  appears 
to  have  some  effect  on  the  myoneural  receptors  in  muscle,  for  it  arrests  the 
twitchings  induced  by  physostigmine  and  in  large  doses  interrupts  the  path 
from  nerve  to  muscle  in  the  same  way  as  curara.  When  injected  intravenously 
magnesium  })roves  to  be  considerably  more  poisonous  than  potassium,  but,  unlike 
the  latter,  kills  by  paralyzing  the  respiration.  None  of  these  effects  are  elicited 
when  magnesium  salts  are  given  by  the  mouth,  as  that  absorbed  is  excreted 
rapidly  and  there  is  never  enough  accumulated  in  the  blood  to  have  any  action. 
Magnesium  is  excreted  by  the  kidney  and  traces  may  appear  in  the  secretions 
from  other  organs.  It  is  "eliminated  rapidly,  almost  the  whole  appearing  in  the 
urine  within  fortj'-eight  hours,  and  this  excretion  of  magnesium  is  attended 
by  an  increase  in  the  calcium  of  the  urine,  while  that  of  the  faeces  may  diminish. 


Bibliography. 

Sne  also  Bibliography  of  Calcium,  Potassium,  Rubidium,  and  Cesium. 
Boehm.     Arch.  f.  exp.  Path.  u.  Pharm.,  iii,  p.  21G. 
Neumann.     Pfliiger's  Arch.,  xxxvi,  p.  576. 
Brunton  and  Cash.     Phil.  Trans,  of  Roy.  Soc,  1884,  i,  p.  223. 
Mcltzer.     Amcr.  Journ.  of  Phys.,  xxi,  p.  449.     (Strontium.) 
Mendel  and  Thacher.     Ibid.,  xi,  p.  5.     (Strontium.) 

Mellzer  and  Auer.     Amer.  .Journ.  of  Physiol.,  xiv,  xxi-xxiii.    Journ.  of  Pharmacology, 
i,  p.  1.    (Magnesium.) 

Mendel  and  Benedict.     Amer.  .Tourn.  Phys.,  xxv,  p.  1.     (Magnesium.) 


L.    SULPHIDES. 

The  ordinary  sulphides  of  the  alkalies  are  of  little  importance  in  theinselves, 
as  they  are  seldom  used  in  therapeutics.  The  effect  of  hydrosulphuric  acid, 
however,  apart  from  its  local  irritant  action,  is  due  to  the  sulphide  which  it 
forms  in  tiie  blood,  and  the  study  of  this  powerful  poison  therefore  involves  a 
preliminary  examination  of  the  effects  of  the  sulphides.  Again,  suli)hur  is  in 
it. self  inert^  tnit  is  changed  to  sulphides  and  hydrosulphiu-ic  acid  in  the  alimentary 
canal,  and  the  effects  induced  by  its  administration  are  due  to  these  bodies, 
and  not  to  Ihe  original  element  (p.  92). 

Action.-Tlie  sulijhidcs  are  very  weak  salts,  for  even  carbonic  acid  is  capable 
of  liberating  hydrosulphuric  acid,  and  wherever  they  come  in  contact  with 
it  in  (luantity  there  is  a  tendency  to  form  free  acid,  which  acts  as  a  powerful 
local  irritant";  it  is  not  impo.ssible  that  the  suli^hides  have  an  irritant  effect  of 
thems(;lves  in  addition  to  that  of  the  hydrosulphuric  acid.  The  sulphides 
accordingly  act  as  irritants  in  the  stomach  and  bowel,  and  in  the  latter  induce 
incrca.sed  peristalsis  and  i)urgation.  When  injected  subcutaiieously  in  the  frog, 
sodium  sulphide  causes  a  narcotic  condition  from  depression  of  the  central 
nervous  .system,  and  in  sufficient  quantities  weakens  the  skeletal  muscle  and  the 
heart,  which  continues  to  beat  after  complete  i)aralysis  has  been  ol)tained, 
hut  eventually  ceases  in  diastole.  After  the  narcosis  has  lasted  for  sonie  time, 
there  follows  a  marked  increase  in  the  reflex  irritability,  with  convulsions  re- 


SULPHIDES  noo 

sembling  those  of  strychiune  poisoning  in  their  general  character,  but  differing 
from  them  in  lasting  continuously  for  weeks  or  even  months  at  a  time.  The 
animal  lies  in  an  extended  and  tense  condition  throughout,  and  passes  into 
complete  opisthotonos  on  being  touched. 

Sulphides  injected  intravenously  in  mammals  induce  violent  convulsions, 
which  seem  to  be  of  cerebral  origin,  for  they  do  not  occur  in  the  hind  limbs 
when  the  spinal  cord  is  cut.  The  respiration  is  at  first  accelerated  and  later 
dyspnoeic  and  finally  ceases,  this,  along  with  the  paralysis  of  the  vasomotor 
centre,  being  the  cause  of  death.  The  heart  does  not  seem  to  be  seriously 
affected  except  indirectly  through  the  failure  of  the  respiration  and  the  fall  of 
the  blood-pressure. 

Sulphide  solutions  added  to  drawn  blood  reduce  the  oxyha-moglobin  at 
once,  and  give  the  blood  a  dark  venous  color.  At  the  same  time  a  compound 
of  sulphide  and  haemoglobin  is  formed,  the  chemistry  of  which  is  still  very 
obscure,  but  which  would  seem  to  be  more  nearly  related  to  methtemoglobin 
than  to  hemoglobin.  It  is  known  as  sulpho-hsemoglobin  or  as  sulpho-methse- 
moglobin,  and  gives  the  blood  a  greenish  color  when  a  thin  layer  is  Examined, 
while  a  thicker  layer  is  dark  red-brown.  This  sulpho-ha?moglobin  possesses 
a  characteristic  spectrum,  marked  by  a  dark  line  in  the  red  to  the  left  of  the 
D  line.  Lai'ger  quantities  give  an  olive-green  color  to  the  blood,  and  the 
spectrum  of  sulpho-hcemoglobin  disappears.  When  sulphides  are  injected 
into  frogs,  and  more  especially  when  sulphuretted  hydrogen  is  inhaled,  the 
blood  gives  the  characteristic  spectrum  during  life,  but  this  does  not  seem 
to  be  the  case  in  mammals,  although  sulpho-hsemoglobin  is  formed  soon  after 
death.  The  blood  changes  are  not  the  cause  of  death  in  poisoning,  as  was 
formerly  supposed,  but  the  direct  action  of  the  sulphides  on  the  central  nervous 
system. 

"  Sulphides  absorbed  into  the  blood  are  rapidly  oxidized,  and  are  excreted 
in  the  urine  in  the  form  of  sulphates  and  of  organic  sulphur  compounds  of 
unknown  constitution.  Small' quantities  escape  by  the  lungs,  and  give  the 
breath  the  disagreeable  odor  of  sulphuretted  hydrogen,  and  according  to  some 
authorities,  some  is  excreted  in  this  form  in  the  perspiration. 

The  sulphides  dissolve  the  horny  epidermis  and  hair  very  readily  when 
they  are  applied  to  the  skin.  If  the  application  is  continued,  some  irritation 
and  redness  is  produced. 

Hydrosulphuric  Acid  (sulphuretted  hydrogen,  hydrogen  sulphide  (HaS)  ) 
is  a  gas  with  strong  irritant  properties,  which  it  shares  with  other  acids  (see 
page  549)  and  has  not  infrequently  given  rise  to  poisoning,  as  it  is  formed  in 
large  quantities  in  the  course  of  the  putrefaction  of  sulphur  compounds,  such  as 
proteins.  Sewer  gas  often  contains  it  in  quantity,  and  workmen  employed  in 
cleansing  sewers  or  cesspools  have  often  suffered  from  its  effects.  When  inhaled 
in  concentrated  form  it  is  almost  immediately  fatal,  the  patient  losing  con- 
sciousness at  once,  and  the  respiration  ceasing  after  a  few  seconds.  In  smaller 
quantities  it  causes  immediate  unconsciousness,  lasting  for  several  hours  and 
then  passing  into  fatal  coma,  which  is  often  interrupted  by  violent  convulsions. 
In  both  of  these  forms  the  symptoms  are  due  to  the  direct  action  of  the  sulphides 
on  the  brain  and  medulla  oblongata.  Persons  exposed  to  a  very  dilute  vapor  of 
sulphuretted  hydrogen  suffer  from  local  irritation  of  the  eyes,  nose  and  throat, 
indicated  by  pain  and  congestion  of  the  conjunctiva,  sneezing,  dryness  and 
soreness  of  the  mouth  and  throat,  and  a  reflex  increase  in  the  secretion  of  tears, 
saliva,  and  mucus.  Headache,  dulness,  giddiness  and  loss  of  energy  are  com- 
plained of;  the  symptoms  frequently  appear  only  some  time  after  the  exposure 
to  the  poison.  According  to  Lehmann,  death  in  animals  exposed  to  these 
dilute  fumes  is  due  in  part  to  oedema  of  the  lungs  caused  by  the  local  irritant 
action.  He  found  that  one  part  of  hydrosulphuric  acid  in  5,000  of  air  was 
sufficient  to  induce  symptoms  in  man,  and  that  an  atmosphere  containing 
one  part  in  2,000  could  be  respired  for  only  a  short  time,  and  gave  rise  to  alarm- 
ing symptoms;  he  supposes  that  about  one  part  of  hydrosulphuric  acid  in 
1,000  parts  of  air  is  sufficient  to  poison  man  fatally  in  a  very  short  time. 


570  SUBSTANCES  ACTING  AFTER  ABSORPTION 

Tlu'  poisonous  effect  of  sulphuretted  hydrogen  is  due  in  part  to  its  local 
initant  action,  in  part  to  its  directly  affecting  the  central  nervous  system. 
'I'lic  cliangos  in  the  l)lood  occur  during  life  only  after  very  concentrated  gas 
is  inlialed,  although  they  may  indicate  the  ])ois()n  after  death  from  more  dilute 
vapor,  for  the  tissues  in  general  tend  to  assunu;  a  green  color  sooner  after  hydro- 
sulphuric  acitl  poisoning  than  in  the  course  of  ordinary  putrefaction. 

Hydrogen  sulphide  is  destructive  to  most  forms  of  life,  even  when  present 
in  comparatively  small  amount.  Even  the  microbes  of  putrefaction,  which 
])roduce  it  themselves,  are  eventually  killed  by  this  gas,  unless  it  escapes  freely. 

Preparations. 

Potnssa  Stdphurata  (B.  P.),  liver  of  sulphur  (Hepar  Sulphuris),  is  a  mixture 
of  poh'sulphides  and  thiosulphides,  often  containing  sulphate  of  potassium. 
It  is  soluble  in  water  and  jjossesses  an  unpleasant  saline  taste,  and  an  odor  of 
hydrogen  sulphide. 

Calx  Sulphurata  (U.  S.  P.,  B.  P.),  sulphurated  lime,  is  another  impure 
preparation  containing  at  least  60  per  cent,  of  calcium  monosulphide  (CaS) 
(50  per  cent.  B.  P.),  with  some  calcium  sulphate  and  charcoal.  It  forms  a 
gravish  })o\vd(>r,  insolubk;  in  water,  and  gives  off  hydrogen  sulphide.    O.OG  G. 

(1  kr.). 

These  preparations  are  seldom  used  internally,  and,  in  fact,  the  sulphurated 
potassium  has  been  found  to  be  a  dangerous  poison,  from  the  hydrogen  sulphide 
given  off  by  it  in  the  bowel  acting  both  locally  and  after  absorption. 

Sulphurated  potassium  is  used  to  a  very  limited  extent  as  an  external  applica- 
tion in  certain  skin  diseases,  particularly  in  acne,  and  to  destro,y  skin  parasites, 
such  as  that  of  scabies.  It  is  used  as  an  ointment  (1  part  to  10  parts),  and  is 
somewhat  irritant. 

Sulphurated  lime  is  used  occasionally  to  remove  hair  and  horny  excrescences, 
both  of  which  it  renders  soft  and  gelatinous,  but  its  frequent  use  is  liable  to 
cause  irritation. 

Many  mineral  springs  contain  hydrogen  sulphide  in  small  amount,  and 
these  have  obtained  wide  celebrity  in  the  treatment  of  various  chronic  respira- 
tory and  skin  diseases  and  in  syphilis,  gout,  rheumatism,  and  chronic  metallic 
l)oisoning  (lead,  mercury).  Most  of  these  springs  are  hot,  and  it  is  open  to 
(luestion  whether  the  small  amount  of  the  gas  contained  in  the  wat(M-  is  of 
ail}'  efficacy,  and  whether  the  heat  of  the  water  antl  the  hygienic  conditions  are 
not  the  true  cause  of  the  improvement  observed  in  these  cases.  Sulphur  baths 
are  also  formed  artificialh'  by  the  addition  of  sulphurated  potassium  (2-S  oz.) 
to  an  ordinary  hot  bath;  a  small  cjuantity  of  acid  is  sometimes  added,  in  order 
to  free  the  hydrogen  suljjhide  more  rajjidly. 

Bibliography. 

Kaufmann'u.  Rosenthal.     Arch.  f.  Anat.  u.  Phys.,  1SG5,  p.  659. 

Lewin.     Virchow's  Arch.,  Ixxiv,  p.  220. 

Lekmann.     Arch.  f.  Hygiene,  xiv,  p.  135. 

J'ohl.     Arch.  f.  cxp.  Path.  u.  Pharm.,  xxii,  p.  1. 

Ilaniack.     Ibid.,  xxxiv,  p.  150;  Ztschr.  f.  phys.  Choiii.,  xxvi,  p.  55S. 

Uachinskii.     Ztschr.  f.  phys.  Chcin.,  xvii,  j).  220. 

Bind.     Trav.  des  Lab.  de  Thcr.  cxp.  de  Geneve,  ii,  p.  242. 

Meyer.     Arch.  f.  exp.  Path.  u.  Pharm.,  xli,  p.  325. 


LI.    CHARCOAL. 

Charcoal,  like  spongy  i)latinum  and  other  ])orous  bodies,  po.ssesses  the 
property  of  accumulating  gases  in  its  interstices  and  thus  ordinarily  contains 
(•onsi(l('ial)I<'  (luaiilitics  of  oxygen.     When   l)rought    into  contact  with  di-com- 


CARBONIC  ACID  571 

posing  matter,  the  oxj'gen  is  released  and  hastens  the  oxidation  of  the  putre- 
fying niass,  while  the' gases  arising  from  tlie  l)a('terial  action  are  adsorbed  by 
the  charcoal,  which  thus  acts  as  a  deodorant.  It  has  no  direct  action  on  tlie 
microbes  of  putrefaction,  but  may  by  introducing  oxygen  favor  the  de\-elop- 
ment  of  the  aerobic  organisms  at  the  expense  of  the  anaerobic.  Besides  gases, 
charcoal  also  absorbs  many  colloid  bodies,  such  as  the  coloring  matter  of  plants 
and  proteins. 

Animal  charcoal  appears  to  possess  no  advantages  over  wood  charcoal,  and 
thev  both  act  when  moist  almost  as  efficiently  as  in  the  dry  state. 

Charcoal  has  no  appreciable  effect  on  the  economy,  apart  from  its  lessening 
the  eructations  of  gas  and  the  flatulence  in  some  cases.  It  passes  through 
the  stomach  and  intestine  unabsorbed,  and  may  in  rare  cases  cause  some 
mechanical  irritation  and  increased  movement.  Charcoal  given  in  a  state  of 
suspension  to  animals  is  said  to  have  been  found  in  the  epithelial  cells  of  the 
intestine  and  even  in  the  bloodvessels,  but  does  not  have  any  effect  attribu- 
table to  its  absorption  in  man.    {Wild.  Med.  Chronicle,  1896). 

Preparations. 

Carbo  Animalis  Purificatus  (U.  S.  P.)  is  prepared  by  boiling  bone-black 
with  hydrochloric  acid  iii  order  to  remove  the  lime  and  other  impurities. 

Carbo  Ligni  (U.  S.  P.,  B.  P.),  charcoal  prepared  from  soft  wood  and  finely 
powdered.    Dose,  U.  S.  P.,  1  G.  (15  grs.). 

Charcoal  is  used  internally  to  remove  the  gases  in  flatulence  and  dyspepsia, 
and  is  prescribed  in  powder  or  in  the  form  of  charcoal  lozenges.  It  may  be 
given  in  any  ciuantitj',  but  is  most  commonly  prescribed  in  4-8  G.  (60-120 
grs.)  doses.  It  is  employed  externally  as  a  deodorant  in  cases  of  foul  ulcers, 
cancerous  sores,  or  malodorous  secretions  from  any  source;  for  this  purpose 
it  is  added  to  poultices  or  used  dry  in  bags  of  fine  cloth. 


LH.     CARBONIC  ACID. 

Carbonic  acid  is  contained  in  considerable  quantity  in  many  thera- 
peutic preparations,  notably  in  the  eflfervescent  cathartics  and  ant- 
acids, and  also  in  many  beverages,  such  as  soda  water,  potash  water, 
champagne,  and  other  sparkling  wines.  In  some  of  these  it  is  formed 
by  the  action  of  an  acid  such  as  citric  or  tartaric  acid  on  carbonates, 
in  others  it  is  liberated  in  the  course  of  fermentation,  while  in  the 
artificial  aerated  waters  it  is  forced  into  solution  under  high  pressure. 
The  last  are  therefore  simple  solutions  of  carbonic  acid,  while  in  the 
others  more  powerful  agencies — cathartic  salts  or  alcohol — are  contained 
in  addition. 

Carbonic  acid  has  a  weak  irritating  action  when  applied  in  ciuantit>-; 
thus  in  baths  charged  with  carbonic  acid,  a  slight  reddening  of  the 
skin  has  been  observed,  and  some  irritation  and  prickling  of  denuded 
surfaces  is  produced;  a  stream  of  carbonic  acid  directed  against  a 
woimd  or  burn  causes  considerable  heat  and  pain.  Pure  carbonic 
acid  gas  causes  spasm  of  the  glottis  when  inlialed,  and  even  when  it  is 
much  diluted,  some  irritation  in  the  respiratory  passages  may  follow^ 
at  first.  Solutions  of  carbonic  acid  induce  reddening  of  the  mucous 
membrane  of  the  mouth  and  stomach,  and  are  ^•ery  rapidly  absorbed, 
owing  to  the  congestion  and  increased  blood  flow  in  the  stomacli  wall 


572  SUnsTAXCES  ACTIXC;   AFTER  ABSORPTION 

whicli  follows  their  administration.  IVIucli  of  the  carbonic  acid  is 
thrown  nj)  hy  eructation,  but  some  of  it  is  absorbed  and  is  excreted  by 
the  lungs.  The  absorbed  acid  has  no  effect  on  the  organism,  but  the 
slight  irritation  of  the  stomach  may  cause  increased  appetite  and  a 
feeling  of  well-being.  The  rapid  absorption  of  the  water  in  which  it  is 
(lissohcd  is  followed  by  an  augmented  secretion  of  urine,  and  the  carbonic 
acid  waters  are  therefore  used  in  preference  to  ordinary  waters  where  a 
rapid  flusliing  of  the  tissues  and  a  profuse  secretion  of  urine  is  desired. 
In  addition,  the  slight  irritation  of  the  mouth  and  stomach  renders  them 
more  acceptable  than  ordinary  waters  in  fever  and  in  other  diseases 
acconii)anied  by  intense  thirst;  a  mixture  of  milk  and  aerated  water 
is  often  very  grateful.  The  presence  of  carbonic  acid  in  the  sparkling 
wines  leads  to  the  rapid  absorption  of  the  alcohol  also,  and  this  action 
on  the  stomach  may  explain  their  being  more  exhilarating  than  other 
wines  containing  an  equal  amount  of  alcohol.  The  slight  irritant 
effect  of  carbonic  acid  in  the  stomach  has  pro\ed  of  benefit  in  some  forms 
of  gastric  catarrh,  such  as  that  following  alcoholic  excess.  Carbonic  acid 
waters  are  also  useful  in  the  vomiting  of  pregnancy  and  in  seasickness. 

The  prolonged  application  of  carbonic  acid  to  the  mucous  mem- 
branes leads  to  local  am^sthesia,  and  numbing  of  the  skin  is  also  stated 
to  occur  under  similar  treatment. 

Carbonic  acid  is  absorbed  from  all  the  mucous  membranes,  from 
the  skin  and  from  the  lungs.  The  gas  has  no  effect  after  absorption 
except  when  inhaled,  however,  as  when  absorbed  in  any  other  way  it 
is  at  once  excreted  by  the  lungs,  and  the  amount  a])sorbed  never  alters 
appreciably  the  normal  percentage  of  carl)onic  acitl  in  the  blood. 

WTien  carbonic  acid  is  inhaled  unmixed  with  oxygen,  it  induces  asphyxia, 
partly  from  a  specific  action  which  it  exerts  on  the  central  nervous  sj-stem, 
but  chiefly  from  the  absence  of  oxygen.  Its  effects  are,  therefore,  very  similar 
to  tliose  of  any  indifferent  gas,  such  as  hydrogen  or  nitrogen,  and  the  symptoms 
are  those  of  ordinary  asphyxia.  When,  however,  carbonic  acid  is  inhaled  mixed 
with  a  sufficient  amount  of  oxygen,  the  specific  effects  of  the  gas  are  ol)served 
without  any  asphyxia.  The  sjniiptoms  are  those  of  transient  stimulation  and 
subsequent  depression  of  the  central  nervous  system  and  heart.  The  first 
stage  is  marked  by  a  very  short  period  of  jjsychical  exaltation,  with  deep  res- 
pirations, a  slight  rise  in  the  blood-pressure  and  a  moderately  slow  pulse.  \'ery 
soon,  however,  unconsciousness,  loss  of  the  spontaneous  movements,  and  later 
of  the  spinal  reflexes  follow,  the  respiration  becomes  somewhat  slower  and 
sliallower,  the  pulse  continues  slow  and  the  heart  is  weaker.  If  the  inhalation 
Ije  continued  the  resj^iration  fails,  the  heart  continuing  to  beat  for  a  short 
t  iine,  though  weakly.  The  symptoms  of  the  first  stage  seem  to  be  due  to  a  direct 
stinmlaiit  action  on  the  cerebrum  and  on  the  vagus,  vasomotor  and  respiratory 
centres,  while  the  second  stage  resembles  that  induced  by  tlio  ordinary  anaes- 
thetics, and  is  evidently  caused  by  depression  of  the  central  ner\ous  system 
and  of  the  heart  muscle.  In  fact  a  mixture  of  carbonic  acid  and  air  has  been 
used  as  an  ana'stlietic  in  one  or  two  surgical  ojjcrations.  Death  from  carbonic 
acid  poisoning  is  not  preceded  by  convulsions,  those  observed  in  ordinary 
asphyxia  being  due  to  the  absence  of  oxygen,  and  not  to  the  excess  of  carbonic 
acid;  it  is  still  undecided  l)y  which  of  (h(>se  factors  (he  increa.sed  peristalsis  seen 
ill  sulTocation  is  caused.  In  well  diluted  vapor  the  symptoms  of  exaltation  alone 
are  (jbs(!rved,  no  aiKesthesia  following     A  mixtin-e  of  .">  jxm-  cent,  carbonic  acid 


CARBONIC   ACID 


573 


ill  ;iir  causes  acceloratiou  and  deepening  of  the  lespiralion  without  further 

changes.  ,      •  i        i 

Carbonic  acid  in  excess  a(;ts  as  a  poison  to  other  organs  besides  the  central 
nervous  system  and  the  h(!art,  although  this  effect  is  not  seen  in  manimals. 
Frog's  muscle  loses  its  irritability  rapidly,  the  ciliated  epithelium  ceases  move- 
ment and  the  motor  nerves,  after  a  short  period  of  increased  excitability,  are 
paralyzed  by  exposure  to  an  atmosphere  of  carbonic  acid.  The  blood  assumes 
the  venous  color  when  shaken  witli  the  gas,  and  prolonged  contact  produces 
acid  hcTmatin,  as  does  any  other  acid.  It  is  a  general  poison  to  the  protoplasm 
in  mammals,  apnvt  from  the  effects  on  the  central  nervous  system,  for  the  com- 
bustion in  the  tissues  is  lessened  to  an  extraordinary  degree,  as  is  evidenced  by 
the  very  small  amount  of  oxygen  absorbed. 

Fig.  69 


Periodic    respiration    in    a    rabbit.      Between    the    arrows,  6    per   cent.    CO2  in    air   was 
inhaled  and  the  respiration  became  regular,  but  relapsed  again  soon  afterward. 

Carbonic  acid  is  the  natural  stimulus  of  the  respiratory  centre,  and  it  has 
been  suggested  as  a  remedy  in  some  forms  of  respiratory  failure;  thus  in  opium 
poisoning  it  would  seem  a  rational  form  of  treatment  to  inhale  5-7  per  cent, 
of  carbonic  acid  in  air.  In  some  forms  of  Cheyne-Stokes  respiration  it  has  been 
found  that  dilute  carbonic  acid  restores  regular  breathing     (Fig.  69). 

Mineral  waters  containing  large  quantities  of  carbonic  acid  in  solution  are 
often  recommended  as  baths  in  various  chronic  diseases,  such  as  rheumatism. 
The  effects  may  be  due  to  the  carbonic  acid  in  part,  but  these  waters  also 
contain  salts  in  solution. 

Solid  carbonic  acid  (carbonic  acid  snow)  has  been  applied  as  an  irritant  in 
various  external  conditions  (page  79)  and  has  also  been  used  to  induce  local 
anaesthesia  by  cold  (page  71). 


Bibliography. 

p.  Bert.     Legons  sur  la  Respiration,  Paris,  1870. 

Quincke.     Arch.  f.  exp.  Path.  u.  Pharm.,  vii,  p.  101. 

Range.     Ibid.,  x,  p.  332. 

Friedlander  u.  Herter.     Ztschr.  f.  phys.  Chem.,  ii,  p.  99. 

Lowy.     Pfliiger's  Arch.,  xlvii,  p.  601. 

Rothschild.     Beitr.  z.  klin.  Chir.,  xxxv,  p.  281. 


574  SUBSTANCES  ACTINCl  AFTER  ABSORPTION 


Lm.    OXYGEN. 

Ever  since  the  discovery  of  tlie  relation  of  oxygen  to  the  respiration,  attenipts 
have  l)ecn  made  to  use  it  in  therapeutics,  l)y  inhahng  tlie  gas  pure  or  mixed 
with  air,  or  by  spending  a  certain  time  each  day  in  chambers  of  compressed 
air.  It  was  expected  that  by  thes{>  means  a  hirger  amount  of  oxygen  would  be 
absorbed,  and  a  more  active  combustion  in  the  tissues  would  be  induced.  The 
oxygen  is  carried  to  the  tissues  for  the  most  part  in  the  form  of  oxyhaMuoglobin, 
a  very  small  fraction  existing  in  simple  solution  in  the  plasma.  Now  in  normal 
conditions  the  air  inhaled  by  the  lungs  suffices  to  saturate  practically  the  whole 
of  the  ha:'moglobin  in  the  pulmonary  vessels  and  the  breathing  of  pure  oxygen 
cannot  appreciably  increase  the  amount  carried  as  oxyhiemoglobin.  It  is  true 
that  the  oxygen  cUssolved  in  th(;  plasma  is  increased  by  a  great  rise  in  the  baro- 
metric pressure,  or  by  inhaling  i)ure  oxygen,  but  this  dissolved  oxygen  is  trifling 
in  amount  compared  with  that  in  combination  with  the  hannoglobin.  Under 
ordinary  conditions,  then,  the  air  is  sufficient  to  oxidize  almost  all  the  reduced 
haemoglobin  passing  through  the  lungs,  and  oxygen  lessens  but  slightly  the  small 
proportion  that  escapes  by  the  pulmonary  veins  unoxidized.  As  far  as  the 
tissues  are  concerned,  the  oxidation  is  of  course  the  same  whether  the  oxyhemo- 
globin carried  to  them  by  the  l)lood  was  formed  in  a  pure  atmosphere  of  oxygen 
or  in  air,  of  which  it  comprises  only  about  20  per  cent.  The  slight  increase  in  the 
oxyhiemoglobin  of  the  blood  has  no  appreciable  effect,  as  more  oxygen  is  offered 
to  the  tissues  normally  than  they  can  assimilate.  It  is  therefore  inconceivable 
that  the  very  slight  increase  in  the  quantity  of  oxygen  in  the  blood  can  have 
any  effect  on  the  oxidation  in  the  tissues  under  ordinary  conditions.  But 
if  the  gas  l)e  inhaled  under  high  pressure  the  augmented  tension  in  the  blood 
may  induce  some  symptoms,  and  this  is,  according  to  Smith,  the  explanation 
of  a  tendency  to  tetanic  convulsions  which  he  found  developed  in  animals 
under  these  circumstances;  hilarity  and  some  other  nervous  effects  are  said 
to  have  been  induced  in  man  in  some  instances,  and  these  may  also  be  inter- 
l^reted  as  the  results  of  the  high  oxygen  tension  in  the  blood,  if  they  were  not 
the  products  of  fancy  and  suggestion.  Oxygen  inhalation  is  th(>refore  incapable 
of  increasing  the  oxidation  in  the  tissues,  or  in  fact  of  modifying  in  any  way  the 
metabolism,  and  experience  has  shown  it  to  be  valueless  in  such  constitutional 
diseases  as  diabetes  and  gout,  in  which,  moreover,  it  has  been  demonstrated 
that  there  is  no  deficiency  in  the  oxygen  of  the  blood. 

The  further  question  arises  whether  oxygen  inhalation  is  likely  to  be  of 
benefit  in  the  cyanosis  due  to  severe  cardiac  or  pulmonary  disease.  Improve- 
ment is  sometimes  observed  clinically,  the  skin  losing  its  dark  color,  and  the 
respii-ation  and  heart  becoming  less  rapid  and  laliored  as  soon  as  the  inhala- 
tion is  conunenced,  and  alarming  symptoms  returning  when  it  is  stopped. 
This  has  been  explained  by  the  larger  amount  of  oxygen  dissolved  in  the  plasma; 
when  air  is  breathed,  the  plasma  contains  only  about  0.6  p(>r  cent,  of  oxygen 
in  simple  solution,  but  when  oxygen  is  inhaled  the  content  may  rise  to  3 
per  cent,  and  this  niay  reinforce  the  oxygen  carried  by  the  luemoglobin.  In 
cases  in  which  only  a  small  (luantity  of  blood  is  passed  through  the  lungs  owing 
to  circulatory  disorder,  or  where  the  aerating  surface  of  the  lungs  is  diminished 
by  exudation,  this  small  supplementary  supi)ly  of  oxygen  may  be  of  importance. 
Another  and  probably  more  important  factor  in  the  improvement  seen  umler 
oxygen  in  i)ulmonary  disease  may  be  the  better  diffusion  of  the  oxygen  in  the 
lung  alveoli;  the  air  actually  inspired  does  not  pass  directly  into  the  alveoh, 
but  diffuses  from  the  wider  air  passages  into  the  narrower  ones  and  then 
reaches  the  absorbent  surfaces.  Pure  oxygen  difiuses  more  rapidly  and  in 
hu-ger  (juaiitity  into  the  alveoli  than  when  it  is  mixeil  with  nitrogen,  and  it  is 
therefore  (•oncei\'al)le  that  when  the  movement  of  the  air  in  the  air  passages 
is  insufficient,  oxyg(Mi  may  give  relief  by  diffusing  in  larger  (juantity  into  the 
alveoli.  Insufficient  movement  of  the  air  currents  may  l)e  due  to  obstruction 
of  Ihc  respiratory  trad,  as  in  asthma  or  severe  l)roncliitis  or  jmenmonia,  or  to 


ox  YGEN  575 

slow  unci  shallow  brciithiiiji;  from  tU'i)r('ssioii  of  the  ceiitro.  Hill  and  Twort 
state  that  when  the  breathing  is  deep  in  normal  persons,  the  oxygen  in  the 
blood  is  not  altered  when  oxygen  is  inhaled  instead  of  air,  but  that  wluni  the 
breathing  is  very  shallow,  much  more  oxygen  is  contained  in  the  blood  during 
oxygen  inhalation.  The  same  increase  may  occur  when  the  breathing  is  insufh- 
cicnt  through  exudation.  Many  observers  have  noted  that  the  pulse  is  slowed 
by  the  inhalation  of  oxygen,  even  when  there  is  no  increase  in  the  oxygen 
absorbed  or  in  the  carbonic  acid  exhaled,  and  the  statement  is  made  that  greater 
exertion  is  possible  under  oxygen  breathing  than  under  air. 

When  the  ha?moglobin  of  the  blood  is  so  altered  as  to  be  incapable  of  trans- 
porting oxygen  to  the  tissues,  as  in  cases  of  poisoning  with  carbon  monoxide, 
nitrites,  chlorates,  nitrobenzol,  etc.,  oxygen  inhalation  is  indicated,  for  it  has 
been  shown  by  Haldane  and  others  that  the  plasma  dissolves  enough  oxygen 
to  maintain  life  when  that  supplied  by  the  blood  corpuscles  is  insufficient.  The 
inhalation  has  to  be  continued  until  the  symptoms  of  deficient  aeration  have 
disappeared. 

Many  microbes  are  killed  or  at  any  rate  much  retarded  in  their  growth 
when  freely  exposed  to  the  air,  and  attempts  have  been  made  to  treat  pul- 
monary phthisis  by  oxygen  inhalation.  The  results  have  been  less  disastrous 
than  those  of  some  of  the  other  treatments  by  inhalation,  but  no  distinct  benefit 
has  accrued,  and  in  some  cases  haemoptysis  has  been  induced  by  it  from  some 
unexplained  cause.  Smith  has  found  that  the  inhalation  of  oxygen  under 
some  pressure  causes  irritation,  congestion  and  consolidation  of  the  lungs  in 
mice  and  birds. 

Oxygen  is  inhaled  through  a  mask  connected  with  a  large  container  which 
is  filled  from  a  tank  of  the  compressed  gas.  Very  often  the  oxygen  may  be 
diluted  with  air  and  for  this  purpose  a  small  opening  may  be  made  in  the  mask. 
Ozone,  or  active  oxygen  (O3),  is  a  much  more  powerful  oxidizing  body  than 
ordinary  oxygen,  but  is  more  easily  reduced  than  peroxide  of  hydrogen.  It 
has  a  curious  phosphorous  odor  and  is  distinctly  irritant  to  the  respiratory 
membranes;  it  is  almost  always  accompanied  by  nitrogen  oxides,  and  these 
may  further  aggravate  this  local  irritation.  It  is  rapidly  decomposed  by  living 
matter,  and  is  certainly  not  absorbed  into  the  blood  unchanged;  in  fact  it  is 
inniiediately  destroyed  in  the  pulmonary  surfaces.  In  man  its  inhalation  in  a 
dilution  of  2-3  per  million  of  air  causes  drowsiness  and  headache  from  irritation 
of  the  frontal  sinus.  In  animals  15-20  parts  of  ozone  per  million  of  air  some- 
times proves  fatal  in  a  few  hours  from  respirator j^  irritation;  a  condition  of 
weakness  and  drowsiness  precedes  death,  apparently  as  a  result  of  the  local 
irritation,  and  the  lessened  movement  is  accompanied  by  a  fall  in  the  CO2 
eliminated.  Ozone  injures  most  enzymes  and  the  fermentation  of  yeast  is 
hindered,  but  the  lactic  fermentation  does  not  seem  to  be  affected  and  some 
others  are  merely  delayed.  Ozone  applied  to  the  seeds  or  leaves  of  the  higher 
plants  also  delays  their  development  and  injures  them. 

Ozone  has  undoubtedly  disinfectant  properties,  but  these  are  only  apparent 
when  air  contains  15  mg.  or  more  per  litre.  Even  this  disinfects  only  the 
air  itself  and  the  surfaces  of  objects,  as  the  ozone  loses  its  oxidizing  properties 
whenever  it  comes  in  contact  with  organic  matter  and  therefore  fails  to  penetrate. 
It  has  recently  been  advocated  to  disinfect  drinking  water,  but  is  efficient 
only  in  fairly  pure  waters,  as  any  organic  matter  is  oxidized  and  thus  absorbs 
the  ozone  and  the  microbes  escape.  For  this  reason  it  cannot  be  used  to  sterilize 
milk  or  food.  Comparatively  low  dilutions  are  sufficient  to  lessen  the  perception 
of  odors,  partly  owing  to  the  smell  of  ozone  itself  and  partly  by  its  action  on  the 
nasal  mucous  membrane. 

Ozone  inhalation  has  been  recommended  in  the  hope  of  increasing  the  oxi- 
dation of  the  tissues,  and  as  an  antiseptic  in  pulmonary  phthisis,  but  its  irritant 
properties  preclude  its  use  here,  and  it  has  been  generally  discarded.  It  was 
supposed  to  be  formed  in  turpentine  oil  on  standing,  and  old  turpentine  oil 
was  therefore  recommended  in  cases  of  phosphorus  poisoning,  with  the  hope 


576  SUBSTANCES  ACTING  AFTER  ABSORPTION 

that  it  would  tend  to  oxidize  the  phosphorus  and  render  it  harmless.  Recent 
investigations  show,  however,  that  no  ozone  is  formed  in  turpentine  oil,  and 
there  is  no  reason  to  suppose  that  the  treatment  is  of  benefit. 

Many  so-called  solutions  of  ozone  contain  only  small  percentages  of  hydro- 
gen ijeroxide  and  no  ozone  proper,  as,  though  the  latter  is  soluble  in  water,  it 
decomposes  verj'^  rapidly,  only  traces  of  it  being  found  in  the  solution  after 
10-1.")  days.    It  breaks  up  into  oxygen,  and  does  not  form  hydrogen  peroxide. 

The  ozone  of  the  air  has  been  appealed  to,  in  order  to  explain  and  advertise 
the  benefits  induced  by  many  watering  places  and  forest  resorts,  but  it  has 
never  been  satisfactorily  proved  that  the  air  in  these  localities  contains  more 
ozone  than  in  other  less  favored  places.  The  curative  agency  is  generally  the 
change  of  scene  and  interests  and  the  dietary. 

Bibliography. 

Smith.     Jourii.  of  Physiol.,  xxii,  p.  307;  xxiv,  p.  19. 

Haldane,  Mahjill,  and  AInvrogordato.     Joura.  of  Physiol.,  xxi,  p.  160. 

Michadis.     Vprhaiidl.  d.  Congresses  f.  inn.  Med.,  1900,  p.  503. 

Sonntag.     Ztschr.  f.  Hygiene,  viii,  p.  95. 

Hasenknopf.     Charite-annalen,  xxviii,  p.  228. 

Durig.     Arch.  f.  Anat.  u.  Phys.,  1903,  Suoplem.,  p.  209. 

Cowl  and  Rogovin.     Ibid.,  1904,  p.  1. 

Hill  and  Macleod.     Proc.  Roy.  Soc.,  Ixx,  p.  455. 
Bohr  and  Maar.     Skand.  Arch.  f.  Phys.,  xvi,  p.  41. 
Hill  and  Flack.     Proc.  Roy.  Soc,  B.  Ixxxiv,  p.  404. 
Jordan  and  Carlson.     Journ.  Amcr.  Med.  Assoc,  1913,  ii,  p.  1007. 
Parkinson.     Journ.  of  Physiol.,  xliv,  p.  54. 

LIV.    PHOSPHORUS. 

In  the  early  part  of  last  century  phosphorus  played  a  very  important 
role  in  therapeutics,  and,  in  fact,  was  regarded  almost  as  a  panacea, 
but  at  present  its  use  is  much  more  restricted,  and  some  doubt  is  enter- 
tained as  to  its  possessing  any  therapeutic  value  whatever.  At  the  same 
time,  it  has  l)een  the  subject  of  much  and  laborious  investigation, 
partly  because  it  has  frequently  gi^•en  rise  to  poisoning,  and  partly 
because  the  study  of  its  eflFects  has  thrown  much  light  on  some  physio- 
logical and  pathological  processes.  It  differs  from  most  poisons  in 
acting  for  the  most  part  on  certain  phases  of  the  animal  metabolism, 
and  it  is  believed  that  the  liver  is  the  chief  seat  of  its  activity. 

Phosphorus  is  absorbed  with  difiiculty,  because  it  is  very  insoluble 
in  water  and  the  body  fluids  and  is  only  slowly  volatilized  at  ordinary 
body  temperature.  Large  masses  of  phosphorus  may  thus  pass  through 
the  alimentary  canal  without  serious  eflFects,  because  they  fail  to  be 
dissolved  and  ab.sorbed.  But  when  it  is  taken  in  a  finely  di\ided  con- 
dition or  in  solution  in  oil,  it  gives  rise  to  symptoms  in  very  small 
quantity,  and  has  been  found  to  induce  fatal  poisoning  in  man  in  doses 
of  0.05-0.1  G.  (1-2  grs.).^  In  these  conditions  it  is  absorbed  partly 
as  vapor,  j)artl\'  in  solution  in  water,  which  dissolves  only  traces,  how- 
ever, and  ])r(»bably  chiclly  in  .solution  in  the  fats  and  oils,  in  which 
it  is  nnicli  more  soluble.     Phosphorus  vapor  is  also  absorbed  by  the 

'  Phosphorus  is  ofU'n  used  in  suicide,  Renorally  in  the  form  of  rat  poison  or  of  match 
hrads.  I'^ach  phosphorus  match  is  estimated  to  carry  3-5  mg.  of  phosphorus,  so  that 
15  liO  match  heads  are  sufficient  to  induce  fatal  poisoning. 


« 


riiosi'iioRUS  577 

luii,i;s,  and  the  syin])t()nis  of  chroiiic  i)()isuiuns  in  match  factories  are 
believed  to  arise  in  this  way.  It  does  not  seem  to  l)e  taken  up  from 
the  skin,  and  lias  in  fact  little  efl'ect  unless  when  rubbed  on  it,  when 
it  ignites  and  gives  rise  to  severe  burns;  phosphorns  burns  do  not 
cause  phosphorus  poisoning,  however,  as  is  sometimes  stated.  The 
red  amorphous  phosphorus  is  much  less  poisonous  than  the  ordinary 
yellow  form,  })ecause  it  is  less  soluble  and  also  less  volatile,  and  conse- 
quently fails  to  be  absorbed. 

Phosphorus  exists  in  the  blood  as  such,  and  the  effects  on  the  tissues 
are  unquestionably  due  to  the  element  itself,  and  not  to  the  oxygen 
or  hydrogen  compounds,  as  has  been  supposed.  Some  phosphuretted 
hydrogen  (PII3)  may  be  formed  in  the  bowel,  but  is  comparatively 
unimportant,  the  great  mass  of  the  phosphorus  being  absorbed  un- 
changed. As  soon  as  it  is  oxidized,  phosphorus  loses  its  specific  action, 
all  of  the  acids  being  comparatively  harmless.  Phosphorus  has  been 
detected  in  the  blood,  and,  it  is  said,  in  some  of  the  excretions. 

It  is  devoid  of  action  on  albumins  in  solution  and  has  no  immediate 
irritant  effects,  such  as  are  seen  in  poisoning  with  the  heavy  metals. 

Symptoms. — ^Yhen  a  poisonous  dose  of  phosphorus  is  swallowed,  no 
effects  are  elicited  as  a  general  rule  for  several  hours.  The  first  symp- 
toms are  pain  and  discomfort  in  the  region  of  the  stomach,  nausea 
and  eructation  of  the  vapor  with  its  characteristic  garlic  odor,  and 
then  vomiting,  the  contents  of  the  stomach  having  the  same  odor,  and 
being-  phosphorescent  in  the  dark.  Later,  bile  may  be  vomited,  and 
some  diarrhoea  may  set  in,  although  this  is  not  a  common  symptom. 
The  nausea  and  vomiting  often  continue  without  further  symptoms 
for  several  days,  but  frequently  disai)pear,  and  the  patient  appar- 
ently recovers,  particularly  if  the  dose  has  been  small,  or  if  most  of  it 
has  been  removed  by  vomiting  or  by  washing  out  the  stomach.  In 
the  course  of  a  few  days,  however,  the  symptoms  recur,  and  are  generally 
accompanied  by  some  jaundice;  the  pain  extends  from  the  stomach 
to  the  liver,  and  soon  to  the  whole  of  the  abdomen.  The  vomited 
matter  no  longer  contains  phosphorus,  but  may  be  bloody.  The  patient 
complains  of  general  weakness  and  faintness;  the  pulse  is  weak,  the 
li\er  extends  far  below  the  ribs,  and  the  urine  shows  characteristic 
changes  (see  page  588);  hcTmorrhages  occur  from  the  nose,  bowel, 
uterus  and  imder  the  skin,  and  eventually  a  condition  of  collapse  and 
fatal  coma  follows.  Convulsions  and  delirium  have  been  observed  in 
a  considerable  proportion  of  cases  towards  the  termination  of  the 
intoxication.  Death  may  occur,  however,  in  the  first  stage  or  early 
in  the  second,  before  complete  exhaustion  is  reached,  and  in  these  cases 
would  seem  to  be  best  explained  by  the  direct  action  of  the  poison  on 
the  heart.  If  only  a  small  quantity  be  swallowed,  or  if  active  thera- 
peutic measures  be  taken  early,  the  patient  may  recover  without  any 
secondary  symptoms,  and  even  when  these  have  followed  the  prognosis 
is  not  hopeless,  for  the  symptoms  slowly  disappear  in  a  certain  i)ro- 
portion  of  cases. 

Exposure  to  the  fumes  of  phosphorus  has  long  been  known  to  give 
37 


:)7S  sriiST.wci'Js  Acrixa  after  absorption 

rise  to  iM'riostitis  and  lU'crosis  of  the  lower  jaw.  The  disease  befj;ins 
from  a  carious  tooth  or  from  some  lesion  of  the  j;um,  and  may  involve 
most  of  the  jaw,  which  becomes  swollen  and  i)ainful  and  eventually 
evacuates  large  quantities  of  pus  with  pieces  of  dead  hone.  This 
necrosis  was  formerly  frequent  in  match  factories,  but  has  become 
rarer  since  amorplious  phosphorus  has  been  substituted  for  the  yellow 
form,'  and  since  greater  attention  has  been  paid  to  the  ventilation  of 
the  factories  ami  to  the  condition  of  the  teeth  of  the  employees. 
Magitot  has  recently  advanced  the  opinion  that  exposure  to  phos- 
phorus fumes  gives  rise  to  a  mild  chronic  form  of  poisoning,  quite 
aside  from  the  necrosis,  which  is  comparatively  rare.  The  symptoms 
are  cachexia,  slight  jaundice,  anjeniia  and  albuminuria,  and  in  more 
ad\anced  cases  chronic  enteritis  and  diarrlura,  bronchitis  and  a  curious 
fragility  of  the  bones. 

Action:  Fatty  Infiltration. — A  very  striking  feature  in  phosphorus 
poisoning,  and  one  that  was  early  recognized  in  its  history,  is  the 
ai)i)earance  of  numerous  fat  globul':s  in  the  cells  of  many  organs, 
notably  hi  those  of  the  liver,  kid;-  . ,  gastric  and  intesthial  glands,  and 
in  the  muscle  fibres  of  the  lieai,  stomach,  intestine,  smaller  arteries, 
and  often  of  the  skeletal  muscles.  This  fat  was  formerly  believed  to 
be  formed  by  the  degeneration  of  the  proteins  of  the  cells  in  wliich 
it  is  found,  but  it  appears  that  it  is  really  ordinary  fat  transported  ' 
from  the  positions  which  it  normally  occupies  and  deposited  in  the 
cells  of  the  liver,  heart,  and  other  organs.  Pfliiger  has  shown  that  the 
total  fat  of  the  body  is  not  increased  by  phosphorus,  and  Rosenberg 
found  that  when  an  animal  has  been  fed  on  foreign  fats  {e.  g.,  a  dog 
upon  mutton  suet)  and  is  tlien  i)oisoned  with  i)hos])horus,  the  fat  found 
in  the  liver  cells  is  that  characteristic  of  the  food  and  not  that  of  the 
poisoned  animal  as  might  be  expected  if  it  were  derived  from  the  proteins. 
l''urther,  T.eathes  has  shown  that  the  fat  found  in  the  li\er  in  phos- 
phorus jjoisoning  possesses  the  cliaracteristics  of  fat  ordinarily  found 
in  the  subcutaneous  deposits  and  not  that  of  the  fat  of  organs,  so  that 
there  is  e\ery  reason  to  regard  it  as  normal  }:)reformed  fat  deposited 
in  unusual  i)ositions,  rather  than  as  a  new  product  of  the  intoxication. 
The  fatty  infiltration  sets  in  only  after  some  time,  and,  in  fact,  accom- 
])anies  the  secondary  symptoms  for  the  most  ])art,  although  the  cells 
of  the  stomach  and  upper  part  of  the  intestine  suffer  sooner,  and  the 
begiiming  of  this  process  is  probably  the  cause  of  the  early  vomiting. 
The  ])rocess  connnences  in  cloudy  swelling  of  the  cells,  followed  by  the 
appearance  of  graiuiles,  which  so(m  develo])  into  fat  globules.  E\en- 
tually  the  degenerated  cells  break  uj)  into  detritus. 

Another  feature  in  ])hosphorus  poisoning,  which  is,  howe\er,  better 
seen  after  repeated  small  doses  than  after  a  single  large  one,  is  the 
Proliferation  of  the  Interstitial  Connective  Tissue  of  the  stomach,  liver 
and    Kidney,    wliidi    linallv    induces   typical    cirrhosis   of  these   organs. 

'  'I'lii'  plinsplioius  scsquisiilphidc  (.I'jSs),  rcfciitly  iiitrodiiceil  in  niutcli  factoiut*,  soonis 
to  l>c  cvrii  safer  (hail  rod  phosijliuius,  for  tlinunh  niimitc  (Hiantitios  of  the  clement  are 
n-lcascd  froiti  il  in  ihc  tissues,  these  are  too  small  to  induce  any  symptoms. 


PHOSPHORUS 


579 


It  was  formerly  su])p()sc(l  that  this  indicated  a  specific  irritant  action 
of  the  phosphorus  vapor  on  the  connective  tissue,  but  many  i)ath- 
ologists  now  regard  this  proHferation  as  a  secondary  result  of  the 
necrosis  of  the  parenchyma  cells.  In  animals  poisoned  by  the  pro- 
longed administration  of  small  quantities  of  phosphorus,  the  ordinary 
effects  of  hepatic  and  renal  cirrhosis  have  been  induced,  such  as  dropsy, 
anaemia,  and  cachexia. 

When  very  minute  quantities  of  phosphorus  are  administered  ^  to 
animals,  no  poisoning  results,  but  according  to  Wegner,  a  specific 
action  on  the  Bones  is  induced,  especially  in  young  animals,  in  which 
the  bones  are  still  growing.  Thus,  in  young  rabbits,  quantities  of 
_i_  _  1.  mg,  given  for  several  weeks  are  found  to  be  followed  by  char- 
acteristic changes  in  the  growth  of  the  long  bones,  apparently  induced 
by  the  phosphorus  acting  as  an  irritant  or  stimulant  to  the  bone- 
forming  cells  (osteoblasts).  Wherever  cancellous  bone  is  being  formed 
from  cartilage,  phosphorus  is  stated  by  Wegner  to  cause  the  deposit 
of  a  layer  w^hich  resembles  the  dense  bone  of  the  shaft  in  the  normal 
animal  in  general  appearance  and  also  histologically.  This  layer  of 
dense  bone  at  the  growing  point  is  at  first  the  only  change  induced, 
but  if  the  treatment  lasts  longer  the  soft  cancellous  bone  which  was 
deposited  before  the  phosphorus  treatment  began  is  gradually  absorbed. 
The  medullary  cavity  of  the  bone  is  thus  enlarged,  and  may,  in  fact, 
extend  into  the  epiphyses,  which  in  the  normal  bone  are  filled  with 
cancellous  tissue,  but  which  now  form  part  of  the  much  lengthened 
cavity.  Eventually  the  whole  of  the  cancellous  bone  may  be  absorbed 
and  a  similar  process  of  absorption  begins  in  the  bone  formed  at  first 
under  phosphorus,  while  the  dense  deposit  is  pushed  further  into  the 
remaining  cartilage.  The  development  of  bone  from  cartilage  is  not 
the  only  process  affected,  however,  for  W' egner  states  that  in  the  bone 
deposited  from  the  periosteum  a  somewhat  similar  change  is  induced, 
as  is  shown  by  its  becoming  denser  and  by  the  Haversian  canals  being 
much  contracted  in  size.  In  full-grown  animals  the  changes  in  the 
bone  are  much  less  distinct,  but  the  lamella^  of  the  spongy  tissue  are 
said  to  be  thickened  by  phosphorus  treatment,  and  in  the  fowl  Wegner 
states  that  the  medullary  cavity  may  be  completely  obliterated  by  the 
deposition  of  hard  bone. 

Kassowitz  took  up  the  investigation  some  twelve  years  later,  and 
observed  the  layer  of  white  dense  bone  described  !)>•  Wegner  at  the  e(lge 
of  the  ossifying  cartilage,  but  he  regards  it  not  as  the  result  of  excessive 
activity  of  the  osteoblasts,  but  as  due  to  a  slower  absorption  of  the  calci- 
fied cartilage  from  a  less  rapid  extension  of  the  bloodvessels  than  is 
normal.  With  large  doses  he  produced  appearances  closely  resembling 
those  of  rickets.  Several  other  investigators  have  observed  changes  in 
the  bones  after  phosphorus,  so  that  there  is  good  reason  to  believe  that 
it  possesses  some  specific  action  on  them,  although  some  writers  failed 
to  obtain  definite  results  and  of  those  who  observed  a  modification  in 
the  growth  no  two  agree  in  the  description  of  the  changes  or  in  their 
interpretation. 


5S0  SLliSTWCKS   ACTlNd   AFTER   ABSORPTION 

'I'liis  si)trific  action  on  the  hone-forming  tissues  and  particuhirly 
on  the  i)eri()steum  may  exphiin  the  necrosis  of  the  jaw  in  match 
factories.  The  view  of  the  hitest  investigators  is  that  microbial 
infection  is  necessary  to  permit  of  the  changes  observed  clinically,  but 
that  i)hosphorus  induces  some  change  in  the  bones  which  predisposes 
them  to  infection  by  the  tubercle  bacillus  and  other  organisms  which 
induce  necrosis.  The  occurrence  of  necrosis  of  the  jaw  is  in  fact  a 
strong  argument  for  the  correctness  of  the  view  that  a  specific  action 
on  bone  exists,  for  under  no  other  poison,  even  when  much  more  irritant 
vapor  is  inhaled,  does  a  similar  process  occur  in  man.  And  a  further 
argument  for  this  specific  action  is  the  fragility  of  the  bones  which 
ocurs  in  a  considerable  ])ercentage  of  workers  in  match  factories.  Here 
the  ])hos])liorus  is  carried  to  the  bones  (femur,  tibia,  radius,  etc.)  in 

Fig.  70 


.1  B 

Section  of  the  head  of  the  femur  in  :i  calf.     A,  normal;    B,  after  treatment  with  minute 
doses  of  phosphorus;  C,  the  cap  of  dense  l)one  at  the  growing  point.     (After  Wegner.) 

•the  blood  and  there  is  no  possibility  of  its  reaching  them  directly  as  in 
the  case  of  the  jaw.  It  seems  ])robable  therefore  that  in  phosphorus 
necrosis  of  the  jaw  the  bone  is  changed  by  the  ])hosi)horus  absorbed  and 
carried  to  it  by  the  blood  and  that  this  change  predis])oses  to  infection 
through  a  diseased  tooth  or  sinus.  The  exact  nature  of  this  action  on 
bone  and  its  relation  to  rickets  and  to  osteomalacia  nuist,  howe\  cr,  be 
left  for  further  research  to  determine. 

Phosphorus  weakens  and  slows  the  Heart  when  it  is  ai)i)lied  to  it 
ilircctly  in  the  frog,  or  by  intravenous  injection  in  manunals.  In 
many  cases  of  acute  poisoning  in  man,  however,  the  heart  does  not 
seem  to  be  seriously  aft'ected  until  very  late,  and  this  is  particularly 
the  case  when  comparatively  small  quantities  have  been  absorbed. 
Jn  those  cases  in  which  large  amounts  are  swallowed  in  solution  or  in 
fine  di\ision,  and  in  which  death  occurs  bcfort^  any  secondary  symp- 


PHOSPHORUS  581 

toms  ha^•e  been  developed,  the  fatal  issue  is  generally  ascribed  to  the 
cardiac  action.  This  direct  action  on  the  heart  must  be  distinguished 
from  the  fatty  degeneration  of  the  cardiac  muscle,  which  is  seen  in 
the  later  stages  of  poisoning,  for  no  degeneration  of  the  heart,  and,  in 
fact,  no  pathological  changes  whatever,  may  be  found  in  those  rapidly 
fatal  cases.  Phosphorus  acts  on  the  heart  muscle  directly,  and  does 
not  seem  to  affect  the  regulating  nerves  in  any  way. 

The  Blood  is  but  little  changed  outside  the  body  by  phosphorus, 
for  though  Araki  states  that  the  htemoglobin  parts  with  oxygen  more 
slowly  than  usual,  the  difference  is  trifling.  In  many  cases  of  fatal 
poisoning  the  blood  is  found  not  to  clot  so  readily  as  usual,  and  some- 
times to  remain  fluid  for  forty-eight  hours  or  more;  this  is  not  a  direct 
effect  of  the  poison,  but  is  secondary  to  the  changes  in  the  intestine  and 
liver,  which  lessen  or  entirely  destroy  the  fibrinogen.  The  amount  of  fat 
in  the  blood  is  considerably  increased  in  phosphorus  poisoning,  owing 
to  the  migration  of  the  fats  from  the  usual  deposits  to  the  liver. 

The  absence  of  clotting  in  the  blood  may  be  a  factor  in  the  haemor- 
rhages which  are  met  with  among  the  symptoms  of  the  second  stage, 
but  the  immediate  cause  of  these  is  the  fatty  degeneration  of  the 
muscular  coat  of  the  smaller  arteries  throughout  the  body.  These 
changes  in  the  bloodvessels  may  perhaps  explain  the  oedema  of  the 
retina,  which  is  seen  in  animals  poisoned  with  phosphorus,  though 
these  have  also  been  attributed  to  some  change  in  the  blood.  Occa- 
sionally gangrene  of  the  extremities  has  been  observed  in  phosphorus 
poisoning,  probably  owing  to  the  changes  in  the  vessel  walls. 

Small  doses  of  phosphorus  generally  increase  the  number  of  the 
red-blood  cells  in  man,  and  even  in  poisoning  a  sudden  or  gradual 
increase  in  these  may  occur,  along  with  a  diminution  of  the  leucocytes. 
The  haemoglobin  is  not  correspondingly  augmented,  however.  In  the 
lower  animals  the  effect  on  the  blood  cells  varies  a  great  deal;  in  the 
dog  an  unusual  number  of  red-blood  cells  appears  to  be  destroyed; 
in  the  rabbit  no  distinct  alteration  in  the  number  of  the  red  cells  but 
some  leucocytosis  has  been  observed,  while  in  fowls  an  increase  in  the 
leucocytes  accompanies  a  marked  destruction  of  the  red  cells;  in  the 
the  frog  the  number  of  red  cells  is  not  reduced. 

The  Bone-marrow  in  chronic  poisoning  is  at  first  hyperaemic,  the  fat 
cells  are  atrophied  and  the  leucoblasts  are  greatly  increased;  later  a 
gelatinous  degeneration  sets  in  with  a  decrease  in  the  number  of  the 
marrow-cells  and  a  corresponding  increase  in  the  connective  tissue. 

The  peripheral  Nerves  and  Muscles  do  not  seem  to  be  affected  in 
phosphorus  poisoning,  except  in  so  far  as  the  latter  undergo  fatty 
infiltration.  An  excised  muscle  lives  almost  as  long  in  salt  solution 
containing  phosphorus  as  in  the  unpoisoned  solution. 

The  Central  Nervous  System  is  also  little  changed  by  phosphorus. 
The  coma  and  convulsions  which  appear  before  death  may  be  due 
rather  to  the  disordered  metabolism  than  to  any  direct  influence,  as  is 
shown  by  the  fact  that  consciousness  is  preserved  throughout  the  first 
stage,  and  as  a  general  rule  until  late  in  the  second. 


5S2  SUBSTANCES  ACTING  AFTER  ABSORPTION 

The  fatty  changes  in  the  epitlieUal  cells  of  the  Stomach  and  Intestine 
exj)lains  the  abdominal  pain,  the  vomiting  and  the  occasional  diarrhcra 
seen  among  the  secondary  symptoms.  The  earlier  ])hases  of  this  action 
may  be  the  canse  of  the  vomiting  and  nansea  of  the  first  stage.  This 
degeneration  occurs  also  when  phosphorus  is  injected  hypodermically, 
and  is  therefore  of  the  same  nature  as  that  in  the  other  organs.  The 
cells  of  tlie  stomach  first  attacked  are  those  of  the  glands,  and  the 
c(»nditi(m  has  been  termed  gastradenitis. 

The  Liver  is  early  involved  in  the  action  of  ])h()si)horus,  and  Fischlcr 
and  Burdach  state  that  the  fatal  dose  is  much  higher  than  usual  in 
animals  in  which  the  poison  is  delayed  in  reaching  that  organ;  the\' 
demonstrated  this  in  dogs  in  which  free  communication  had  been 
established  between  the  i)ortal  vein  and  the  inferior  cava,  so  that 
the  li\cr  circulation  was  reduced  to  the  hepatic  artery. 

The  fatty  changes  in  the  liver  cause  a  considerable  increase  in  the 
area  of  hepatic  dulness,  and  at  the  same  time  induce  some  pain  and 
tenderness  over  the  organ. 

In  the  earlier  ])hases  the  secretion  of  bile  i)igment  is  increased, 
denoting  an  unwonted  activity  of  the  liver,  but  later  as  the  cells 
become  infiltrated  with  fat,  they  press  on  the  bile  capillaries  and 
occlude  them,  so  that  the  bile  is  absorbed  into  the  bloodvessels  and 
gives  rise  to  jaundice.  The  secretion  at  this  stage  is  clouded,  viscous 
and  not  deejjly  pigmented,  and  ap])ears  to  be  derived  mainly  from 
the  mucus  cells  of  the  smaller  bile  ducts  and  not  from  the  liver  cells 
])roper.  During  recovery  the  cells  lessen  in  size  and  cease  to  press 
on  the  ducts,  and  the  bile  loses  its  turbidity  and  viscosity,  and  is  very 
dark  in  color,  because  the  pigment  which  was  deposited  in  the  tissues 
during  the  second  stage  is  reabsorbed  and  excreted;  the  jaundice  color 
of  course  disaj^ijcars  from  the  skin  as  the  bile  i)igment  is  reabsorbed. 
Another  factor  in  the  jaundice  may  be  the  destruction  of  the  red  cells 
of  the  blood  and  consequent  increase  of  pigment  formation  in  the  liver. 
This  can  i)lay  only  a  small  jKxrt,  however,  for  jaundice  is  a  conuuon 
symptom  in  man,  but  there  is  no  evidence  tliat  the  red  cells  are  dim- 
inished in  luunber.  The  bile  very  often  contains  albumin  in  consider- 
able amount  while  the  bile  salts  are  reduced;  in  the  later  stages  retl 
blood  cells  may  occur  in  it. 

Other  changes  have  been  shown  to  occur  in  the  li\cr  in  ])hso])horus 
Ijoisoiiiiig;  thus  the  ])roportion  of  water  is  increased  while  the  glycogen 
and  lecithin  are  reduced.  When  the  distribution  of  the  nitrogen  is 
examined,  it  is  found  that  a  smaller  i^roportion  than  usual  is  combined 
in  the  form  of  i)roteins,  while  a  larger  jxTccntagc  is  found  in  the  form 
of  simi)ler  bodies  such  as  anunonia  and  the  amino-acids.  \Vhcn  the 
liver  of  an  uni)oisoned  animal  is  kept  from  ])utrcfaction  for  some  time, 
the  tissue  is  broken  down  by  the  action  of  an  autolytic  ferment;  in 
I)hos])horus  jjoisoning  it  undergoes  the  same  changes  when  preserved 
from  imtrcfaction,  but  the  autolysis  i)rogresses  nuich  more  rapidly. 
Jacob.N-  therefore  infers  that  phosphorus  augments  the  activity  of  the 
autolytic  ferment  of  the  liver  and  thus  reduces  the  i)roteins,  glycogen 


PHOSPHORUS  583 

and  lecithins,  while  inereasinji;  the  simpler  aniino-acids.  The  acid 
formed  in  this  i)rocess  combines  with  ammonia.  The  ferments  which 
decompose  the  amino-acids  do  not  seem  more  active  in  i)hosphorus 
poisoning  or  in  autolysis  than  normally,  but  only  those  which  decompose 
the  proteins  to  their  simpler  bodies.  He  rej2;ards  the  disappearance  of  the 
fibrinogen  of  the  blood  as  a  further  effect  of  this  liver  autolysis,  for  he 
found  that  the  injection  of  the  autolytic  ferment  into  normal  animals 
prevented  coagulation. 

Much  attention  has  been  directed  recently  to  the  rapid  disappearance 
of  the  glycogen  of  the  liver  in  ])hosphorus  poisoning;  this  is  said  to 
precede  the  other  changes  in  the  liver  cells.  When  the  glycogen  of  the 
liver  is  taken  up  under  other  conditions,  it  is  either  rapidly  utilized 
as  a  source  of  energy  under  some  special  strain,  or  it  gives  rise  to  an 
excess  of  sugar  in  the  blood.  In  phosphorus  poisoning  there  is  no 
special  demand  for  carbohj^lrate  which  would  be  satisfied  by  the 
liberation  and  oxidation  of  sugar,  and  on  the  other  hand  there  is  no 
increase  in  the  sugar  of  the  blood,  but  rather  a  decrease.  It  has  therefore 
been  suggested  that  the  glycogen  is  broken  up  with  the  formation  of 
lactic  acid  owing  to  a  specific  action  of  phosphorus  on  the  li^■e^  cells. 

In  the  Kidney,  the  fatty  degeneration  of  the  epithelium  may  account 
for  the  albimiinuria,  which  is  not  generally  severe,  and  is  not  infre- 
quently absent  in  cases  of  poisoning.  Fatty  casts  and  even  globules 
of  fat  are  often  found  in  the  urine  in  cases  which  run  a  chronic  course. 
Blood  and  hemoglobin  may  also  appear  in  it  from  haemorrhages  into 
the  kidney.  The  urine  is  normal  in  quantity  in  the  early  stages  of  the 
intoxication,  but  afterward  becomes  deficient,  and  toward  death  com- 
plete anuria  may  be  observed. 

The  nitrogen  of  the  urine  varies  considerably  in  different  cases. 
Very  often  in  the  first  few  days  after  the  ingestion  of  the  poison,  it  is 
markedly  diminished  in  amount  from  the  prolonged  nausea  and  vom- 
iting, which  prevents  the  absorption  of  food;  the  nitrogenous  excretion 
thus  corresponds  to  that  during  the  first  few  days  of  starvation.  After 
this,  the  nitrogen  of  the  urine  rises  above  what  is  usually  excreted  in 
starvation,  even  though  the  patient  continues  to  fast.  This  increase  is 
almost  entirely  confined  to  the  ammonia  of  the  urine,  which  is  excreted 
as  ammonium  lactate,  and  the  rise  in  the  nitrogen  elimination  therefore 
seems  due  for  the  most  part  to  the  formation  of  lactic  acid  in  excess 
in  the  tissues. 

Some  increase  in  the  other  nitrogenous  constituents  of  the  urine 
also  occurs  in  phosphorus  poisoning,  and  a  number  of  amino-acids 
have  been  identified  in  it.  The  best  known  of  these  are  tyrosin  and 
leucin  crystals,  which  are  not  always  present  in  the  urine,  however, 
although  they  haxe  been  found  in  the  blood  in  some  quantity.  Bau- 
mann  found  an  increase  in  the  substances  of  the  aromatic  series  in 
the  urine.  The  phosphates  of  the  urine  are  often  very  considerably 
augmented,  but  not  because  of  the  excretion  of  phosphorus  as  phos- 
phates, for  the  qnantit>'  absorbed  is  too  small  to  cause  any  ai)preciable 
change.    The  increase  in  the  ])h()S])hatcs  is  rather  to  be  ascribed  to  an 


r.S4  SUBSTANCES  ACTING  AFTER  ABSORPTION 

aiif^iiR'nted  waste  of  the  tissues,  and  the  sulphates  are  also  excreted 
in  liir^'er  quantity  for  the  same  reason. 

When  icterus  is  present,  the  urine  may  be  dark  in  color  from  the 
l.ilc  pi^Mncnt  excreted,  and  bile  acids  are  also  often  contained   in   it. 

Metabohsm. — The  great  similarity  between  the  results  of  normal 
autolysis  and  of  phos])horus  poisoning  has  led  to  the  view  that  the 
essential  effect  of  phosphorus  is  an  acceleration  of  the  autolytic  process, 
which  occurs  in  normal  cells.  This  accelerated  destructive  metabolism 
is  less  completely  carried  out  than  normally,  so  that  intermediate 
products,  such  as  leucin,  tyrosin  and  other  amino-acids  appear  in  large 
quantities  in  the  organs  and  often  in  the  excretions;  lactic  acid  is 
similarly  a  product  of  autolysis,  which  fails  to  be  oxidized  to  carbonic 
acid  as  in  the  normal  body.  This  accelerated  autolysis  occurs  not  only 
in  the  liver  but  also  in  other  organs,  although  in  a  less  marked  degree. 

According  to  this  view,  the  fatty  infiltration  is  a  secondary  result 
of  the  accelerated  autolysis;  the  cells  are  supposed  to  absorb  fat  from 
the  blood  more  rapidly  than  normally  and  to  store  it  in  their  interior 
in  the  form  of  globides,  and  as  the  fat  of  the  blood  is  thus  reduced,  the 
normal  fat  deposits  in  the  body  are  drawn  upon  to  replace  it  and  this 
results  in  the  transference  of  fats  from  the  subcutaneous  tissues  to 
such  organs  as  the  liver,  kidney,  and  heart.  But  these  ha^•e  lost  to  a 
large  extent  their  normal  capacity  of  decom])osing  fats,  which  are 
therefore  deposited  in  the  cells  in  the  same  forms  as  occur  in  the 
normal  adipose  tissue. 

Another  view  has  recently  been  suggested,  that  the  essential  feature 
in  phosphorus  poisoning  in  the  change  in  the  carbohydrate  metabolism; 
the  liver  forms  lactic  acid  from  its  glycogen  which  it  can  no  longer 
retain,  and  this  lactic  acid  is  neutralized  by  ammonia.  The  loss  of 
carbohydrate  causes  a  draft  to  l)e  made  on  the  proteins  of  the  body, 
and  an  increase  in  the  nitrogen  excretion  is  the  result.  At  the  same 
time  the  want  of  carbohydrate  in  the  liver  leads  to  the  mobilization 
of  the  fats,  which  stream  into  the  liver  to  sup})ly  the  deficiency ;  but 
they  can  no  longer  be  utilized  completely  and  are  therefore  deposited 
in  the  cells.  The  theory  is  attractive  from  its  simplicity,  but  is  not 
sufficiently  established  by  experiment,  and  ai)i)cars  to  neglect  several 
accurate  obser^•ations  in  which  the  protein  waste  w^as  shown  to  be 
greater  in  ])hos])horus  poisoning  than  in  complete  starvation. 

In  view  of  the  curious  effect  of  ph()sj)liorus  on  the  tissue  change  of 
the  vertebrates,  its  action  upon  sim])lcr  forms  jjosscsses  some  interest. 
It  has  been  found,  however,  that  yeast,  infusoria  and  bacteria  are  very 
little  affected  by  the  presence  of  this  poison,  and  living  microbes  are 
found  in  large  numbers  on  solid  pieces  of  phosphorus.  The  ferments 
are  also  nnall'ected  for  the  most  ])art,  ])epsin  and  ])ancreatin  acting  in 
the  presence  of  i)hos])liorus.  'J^hc  synthesis  of  hi])i)uric  acid  in  the 
kidney  is  lessened  if  to  tlie  blood  useil  to  perfuse  the  organ  some  phos- 
phorus is  adth'd. 

The  Temperature  is  often  low  in  the  later  stages  of  phosi)horus 
poisoning,  but  sHght  fcNcr  is  also  observed  in  some  cases. 


PHOSPHORUS  5S5 

The  Fate  of  phosphorus  in  the  body  is  still  obscure.  It  is  possible 
that  some  of  it  is  oxidized  to  phosphoric  acid;  and  some  phosi)horus  is 
said  to  be  excreted  by  the  lungs,  although  the  statement  that  the  breath 
becomes  phosphorescent  seems  to  be  extremely  improbable.  It  is  also 
excreted  in  the  urine  in  some  organic  combinations,  of  which  nothing 
is  known,  though  they  are  said  to  be  volatile.  In  pregnant  animals 
poisoned  with  phosphorus  the  foetus  is  found  to  undergo  fatty  degen- 
eration, so  that  the  poison  would  seem  to  pass  through  the  placenta. 
Phosphorus  injected  hypodermically  acts  much  more  slowly  than  when 
swallowed. 

Phosphuretted  hydrogen  (PH3)  induces  the  same  symptoms  as 
phosphorus,  when  it  is  given  in  repeated  small  quantities.  Large 
doses  are  very  rapidly  fatal,  and  the  symptoms  differ  entirely  from 
those  of  phosphorus  poisoning,  consisting  of  marked  dyspnoea,  purga- 
tion, weakness,  tremor,  and  finally  violent  convulsions  and  respiratory 
failure.  The  oxygen  compounds  do  not  seem  to  have  any  such  effects, 
and  for  the  most  part  are  harmless  except  in  very  large  doses. 

Prepaeations. 

Phosphorus  (U.  S.  P.,  B.  P.),  a  translucent,  nearly  colorless  solid  resembling 
wax  in  lustre  and  consistency.  It  emits  wliite  fumes  in  the  air,  which  are 
luminous  in  the  dark  and  take  fire  spontaneously.  The  fumes  have  the  odor 
of  garhc  and  in  dilute  solution  phosphorus  has  a  harsh,  disagreeable  taste. 
It  is  very  little  soluble  in  water,  more  so  in  alcohol,  and  dissolves  to  about  two 
per  cent,  in  fats  and  oils.    0.5  mg.  {^h  gr-)-    (B.  P.  jho-h  gr-)- 

Oleum  Phosphoratum  (B.  P.)  is  a  1  per  cent,  solution  in  almond  oil  and  ether 
(1-5  mins.).  Phosphorated  oil  ought  to  be  freshly  prepared  and  kept  in  tightly 
stoppered  bottles;  solutions  of  1  per  cent,  tend  to  lose  their  strength  by  evapora- 
tion of  the  phosphorus  and  by  oxidation,  when  the  bottle  contains  air.  It  is 
said  to  keep  better  in  more  dilute  solution  (one  per  mille).  It  is  probable  that 
much  of  the  oil  dispensed  is  under  1  per  cent,  in  strength. 

Pihdce  Phosphori  (U.  S.  P.),  each  pill  contains  0.6  mg.  of  phosphorus  (jU 
gr.).    Dose,  1  pill. 

Pilula  Phosphori  (B.  P.),  1  per  cent.,  1-4  grs. 

Therapeutic  Uses. — Phosphorus  has  been  recommended  in  various 
diseases  of  the  central  nervous  system  and  in  neuralgia,  but  it  is  still 
questionable  whether  it  is  of  any  real  benefit  in  these.  There  is  more 
reason  to  believe  in  its  virtues  in  bone  disease,  more  especially  in 
rachitis  and  osteomalacia,  for  in  a  nmnber  of  instances  marked  im- 
provement has  been  observed  in  these  diseases  under  its  use.  It  is 
generally  given  in  solution  in  cod-liver  oil,  and  the  benefit  may  be  due 
in  part  to  the  menstruum,  but  not  entirely,  for  Sternberg  observed  a 
relapse  in  a  case  of  osteomalacia  when  pure  cod-liver  oil  was  substi- 
tuted for  the  phosphorated  oil.  In  rickets  a  solution  containing  0.01 
G.  in  100  CO.  of  cod-liver  oil  is  recommended;  2-4  teaspoonfuls  to 
be  given  each  day.^    In  osteomalacia  a  1  per  cent,    solution  may  be 

1  This  would  be  equivalent  to  |-2  mg.  of  phosphorus  daily,  but  as  a  matter  of  fact 
the  phosphorated  oil  from  which  the  prescription  is  filled  contains  much  less  than  one 
per  cent.,  so  that  the  dose  actually  taken  probably  seldom  amounts  to  more  than  1  mg. 
daily. 


5m;  substances  acting  after  absorption 

nroscrihed  and  l-o  ms.  ])]iospliorus  taken  each  day.  A  number  of 
(.l)S(T\er.s  have  found  that  in  cases  of  rickets  and  osteomahicia  more 
lime  was  retained  under  i)lu)sphorus  treatment  than  usual,  the  ])ropor- 
lion  (»f  the  hme  of  the  food  which  was  excreted  falHng  rapidly.    . 

Other  i)()ne  diseases,  such  as  caries  and  ununited  fractures  have, 
also  been  treated  with  ])hos])horus  occasionally,  but  the  results  have 
not  been  recorded  in  sufficient  numbers  to  allow  of  any  statement  as 
to  the  efficacy  of  the  treatment. 

Treatment  of  Phosphorus  Poisoning. — Phosphorus  is  comparati\ely 
slowly  absorbed  from  the  alimentary  canal,  so  that  in  the  early  stages 
an  attempt  ouglit  to  be  made  to  remove  it  })y  emetics  or  the  stomach 
tube,  and  by  purges.  Fats  and  oils  must  be  avoided,  as  they  tend  to 
dissolve  the  poison  and  promote  its  absorption.  Pliosphorus  has  been 
fomul  in  the  stools  three  days  after  its  ingestion,  and  a  sharp  ]Mirge 
ma\-  therefore  be  of  use  up  to  this  time. 

Another  method  of  treatment  is  that  aiming  at  the  oxidation  of  the 
phos]ihorus  in  the  stomach,  or  at  the  formation  of  unabsorbable  com- 
l)ounds.  Turpentine  oil  was  formerly  used  with  the  object  of  oxidiz- 
ing the  phosphorus  or  of  forming  some  compound  with  it  in  the  stomach, 
but  this  treatment  has  proved  quite  valueless  (Plavec).  Suli)hate 
of  copper  is  recommended  in  phosphorus  poisoning,  a  large  dose  being 
given  first  as  an  emetic,  and  afterward  smaller  doses  to  form  an  insoluble 
compound,  copi)er  phosphide.  Permanganate  of  potassium  solution, 
one  ])er  mille,  has  been  recently  advised  to  oxidize  the  phosphorus, 
while  peroxide  of  hydrogen  solution  is  of  less  value.  In  the  secondary 
stage  alkalies  are  recommended  in  order  to  neutralize  the  excess  of 
lactic  acid  formed  in  the  tissues. 

Phosphorus  necrosis  has  to  be  treated  surgically  on  the  same  prin- 
ciples as  other  necroses  of  bone. 

Bibliography. 

Wegner.     Virchow's  Arch.,  Iv,  p.  11. 

Kassowitz.     Ztschr.  f.  klin.  Med.,  vii,  p.  3G. 

Sternberg.     Ibid.,  xxii,  p.  265. 

Slubenrauch.     Arch.  f.  klin.  Chir.,  lix,  p.  144;    Ixi,  p.  547. 

Jacoby.     Zcitschr.  f.  physiol.  Chi;m.,  xxx,  p.  174. 

Porges  and  Pribram.     Arch.  f.  exp.  Path.  u.  Pharin.,  lix,  p.  20. 

Rey.     Deutsch.  med.  Woch.,  1895,  p.  569. 

Sladelmann.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxiv,  p.  270. 

Aufrecht.     Deutsch.  Arch.  f.  klin.  Med.,  xxiii,  p.  331. 

Ackermann.     Virchow's  Arch.,  cxv,  p.  216. 

Slolnickow.     Arch.  f.  Anat.  u.  Phys.,  1887.    Supplement,  p.  1. 

SchuUze.     Virchow's  Arch.,  cii,  p.  299. 

Plavec.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlviii,  p.  150;    PfliiKcr's  Arch.,  civ,  p.  1. 

Miura.     Virchow's  Arch.,  xcvi,  p.  54. 

SchuUzen  u.  /ij'es.s.     Aniialen  der  Charitc,  xv,  p.  1. 

Fraenkel.     Berl.  klin.  Woch.,  1878,  p.  265;    Virchow's  Arch.,  Ixvii,  p.  278. 

Munzer.     Deutsch.  Arch.  f.  klin.  Med.,  lii,  p.  199. 

Tau.inig.     Arch.  f.  exjj.  Path.  u.  PIi.Trni.,  xxx,  p.  KJl. 

Ilauser.     Ibid.,  xxxvi,  p.  165. 

Pilzvckcr.     Zl.sch.  f.  physiol.  Clicm.,  xli,  j).  157. 

Athannsiu.      Pfli'incr's  Arch.,  ixxiv,  p.  .511. 

Tiiylitr.     Journ.  of  10x|).  Med.,  iv,  p.  399;    Joiirn.  of  Med.  Research,  ix. 


ARSENIC  587 

Stockman  and  Charleris.     Jouin.  of  Path,  and  Baot.,  1903,  p.  205. 

Thayer  and  Wolf.     Journ.  of  Med.  Research,  ix,  pp.  191,  21(). 

Jokote.     Arch.  f.  Hygiene,  xlix,  p.  275. 

Rosenfcld.     Cong.  f.  inn.  Med.,  xv,  p.  427. 

Lindemann.     Arch.  f.  exp.  Path.  u.  Pharni.,  xh,  p.  191;  Ztschr.  f.  Biol.,  xxxix. 

Steinhaus.     Ziegler's  Beitrage  z.  path.  Anatomie,  xxii,  p.  466. 

Monti,  Slick,  Frdnkel,  Zweifel,  Kassowitz.     Wiener  klin.  Woch.,  1901. 

Frank  u.  Isaac.     Arch.  f.  exp.  Path.,  Ixiv,  p.  274. 

Fischler  u.  Burdach.     Zeitschr.  f.  phys.  Chem.,  Ixxviii,  p.  435. 

LV.     ARSENIC. 

Some  of  the  less  active  preparations  of  arsenic,  such  as  the  sul- 
phides, Realgar  (AsoSo)  and  Orpiment  (AsoSs),  have  been  known  in 
therapeutics  since  the  beginning  of  the  Christian  era,  but  this  metal 
was  brought  into  especial  prominence  in  later  times  through  the  fre- 
quent use  of  the  more  dangerous  oxides  in  criminal  poisoning.  Thus 
the  notorious  Aqua  Tofana  of  the  sixteenth  and  seventeenth  centuries, 
owed  its  activity  to  the  presence  of  arsenic,  and  various  arsenical  com- 
pounds have  been  used  up  to  the  last  few  years  more  largely  than 
almost  any  other  poison  in  suicide  and  homicide.  This  is  to  be  ex- 
plained by  their  having  been  widely  employed  in  the  arts,  and  thus 
l3eing  readily  accessible  to  all,  and  by  the  general  recognition  of  their 
poisonous  nature.  Of  late  years  intentional  arsenic  poisoning  has 
become  somewhat  less  common,  though  on  the  other  hand,  accidental 
poisoning  is  still  met  with  not  infrequently,  especially  in  the  chronic 
forms.  ]Many  of  these  chronic  cases  are  extremely  difficult  to  diagnose, 
and  probably  often  pass  unrecognized  by  the  attending  physician. 
In  view  of  this  fact  it  seems  desirable  that  more  stringent  measures 
should  be  taken  to  reduce  the  use  of  arsenic  in  the  arts,  and  especially 
to  prevent  its  being  brought  in  contact  with  food.  The  danger  of 
the  use  of  the  green  arsenical  dyes,  such  as  Scheele's  Green  (arsenite 
of  copper),  and  Schweinfurt's  Green,  or  Paris  Green  (arsenite  and 
acetate  of  copper),  is  now  generally  recognized,  but  arsenic  is  still  used 
in  the  preparation  of  other  colors,  and  these  may  give  rise  to  poisoning 
from  the  imperfect  removal  of  the  metal.  It  has  also  been  used  in  dilute 
solution  to  preserve  food,  and  a  solution  is  often  sprayed  upon  grape 
vines  and  other  plants  to  preserve  them  from  the  attacks  of  insects. 
Poisoning  has  occurred  from  these  sources  and  is  difficult  to  diagnose, 
as  it  is  in  some  cases  impossible  to  find  the  means  by  which  the  arsenic 
enters  the  system.  A  widespread  epidemic  of  poisoning  in  England 
in  1900  drew  attention  to  a  source  of  arsenic  which  up  to  that  time 
had  not  received  the  attention  it  merited.  Several  thousands  of  i)ersons 
suffered  from  arsenic  being  contained  in  cheap  beers  made  from  glucose, 
in  the  manufacture  of  which  sulphuric  acid  had  been  employed.  The 
sulphuric  acid  was  formed  from  iron  pyrites  containing  arsenic,  and  the 
poison  was  carried  from  the  suli)huric  acid  with  the  glucose  into  the 
beer.  Sulphuric  acid  is  used  in  the  manufacture  of  so  many  drugs, 
foods  and  other  substances  in  constant  use,  that  this  intimation  that  it 
may  convey  arsenic  into  articles  where  its  existence  has  not  hitherto 
been  suspected,  is  of  the  gravest  importance. 


5,S,S  SUBSTANCES  ACTIXC  AFTER  ABSORPTION 

MvUxWu'  arsenic  is  insoluble  in  water,  and  passes  through  the 
aliraentarv  canal  for  the  most  part  unchanged  and  without  action, 
'i)ut  it  is  possible  that  small  quantities  may  be  oxidized  to  arsenious 
acid  in  the  stomach  and  intestine  under  some  conditions.  Some 
symptoms  have  been  observed  when  it  is  rubbed  on  the  skin  in  a  state 
of  fine  division,  and  these  are  probably  due  to  its  absorption  in  the 
form  of  an  oxide.  The  characteristic  "arsenic"  action  is  induced  by 
the  salts  of  arsenious  acid  (AsOjHs),  and  by  its  anhydride  (AS2O3), 
which  is  often  known  as  arsenic,  and  which  exists  in  the  tissues  as 
arsenites.  Arsenic  action  is  therefore  due,  not  to  the  element,  but  to 
the  ion  of  arsenious  acid.  The  anhydride  and  salts  of  arsenic  acid 
(II3ASO4)  cause  similar  symptoms,  but  are  less  poisonous  and  act 
more  slowly  than  those  of  arsenious  acid,  and  may  probably  owe  their 
efi'ects  to  the  formation  of  arsenites  in  the  tissues.  The  action  being 
due  to  the  ion  and  not  to  the  element,  it  necessarily  follows  that  com- 
])ounds  from  which  the  ion  is  not  liberated  do  not  induce  the  arsenic 
action,  or  do  so  only  when  they  are  changed  to  bodies  which  can  dis- 
sociate the  arsenious  acid  ion.  Thus  organic  arsenic  combinations  in 
which  the  metallic  atom  is  directly  attached  to  carbon  are  only  feebly 
poisonous,  but  in  course  of  time  seem  to  be  changed  to  arsenious  acid 
in  the  tissues,  and  then  cause  typical  poisoning. 

Arsenious  acid,  which  in  the  following  pages  will  be  taken  as  the 
representative  of  "arsenic"  action,  has  a  faint  sweetish  taste,  and  is 
therefore  not  so  likely  to  be  detected  by  the  victim  as  many  of  the 
other  poisons. 

Symptoms. — In  large  quantities  arsenic  very  often  causes  no  symp- 
toms for  half  an  hour  or  more,  but  then  the  patient  comi)lains  of  a 
feeling  of  constriction  in  the  throat,  of  difficulty  in  swallowing,  and 
of  discomfort  in  the  stomach  region.  This  soon  increases  to  violent 
pain,  and  is  accompanied  by  ^•omiting,  and  later  by  watery  diarrha^a. 
The  stools  are  at  first  of  ordinary  diarrhoeic  appearance,  but  later 
resemble  the  "  rice-water"  stools  of  cholera,  in  that  they  consist  almost 
entirely  of  minute  shreds  of  disintegrated  mucous  membrane  sus- 
jx'iidcd  in  a  serous  fluid;  sometimes,  however,  they  are  clear  and 
gelatinous  in  appearance.  In  some  cases,  blood  appears  in  the  vomited 
matter  and  also  in  the  stools,  but  this  is  not  by  any  means  an  in\ari- 
able  feature.  The  urine  is  diminished,  or  entirely  suppressed,  from  the 
great  amount  of  fluid  eliminated  by  the  stomach  and  bowel.  These 
symi)toms  from  the  alimentary  tract  are  accompanied  by  giddiness, 
cramps  in  the  muscles,  headache,  and  soon  l)y  collapse,  with  cold 
damp  skin,  pallor,  feeble  pulse  and  weak,  sighing  respiration;  this 
later  jxisses  into  coma,  and  death  follows  with  or  without  convulsions. 
In  cases  in  which  the  dose  is  smaller  than  the  fatal  one,  or  in  which  much 
of  the  poison  is  eliminated  by  vomiting,  the  patient  may  recover  with- 
out further  symptoms  than  those  already  described.  Frequently,  how- 
ever, he  recovers  from  the  acute  symptoms  only  to  develop  those  of 
chronic  arsenical  i>oisoning.  In  some  instances  it  is  said  that  no  symp- 
toms arc  present  c\(('])t  those  of  collajjse  and  coma.    In  acute  poisoning 


ARSENIC  589 

death  may  occur  within  '24  hours,  but  more  freciuently  tlie  patient 
Uves  for  2-4  days  longer,  and  then  succumbs  to  exhaustion.  The  fatal 
dose  is  very  uncertain,  because  arsenic  is  very  insoluble,  and  much  of 
the  poison  may  be  thrown  up  by  ^'omiting,  or  pass  out  in  the  stools 
unabsorbed.  Thus  in  some  cases,  recovery  has  followed  after  very  large 
quantities,  while  in  others  about  0.1  G.  (1|  grs.)  has  proved  fatal. 

Chronic  Arsenic  Poisoning  may  arise  from  a  single  large  dose,  the 
effects  persisting  for  weeks  or  months  after  the  ingestion  and  new 
symptoms  arising  as  the  earlier  ones  disappear;  more  frequently,  how- 
ever, it  is  induced  by  the  prolonged  absorption  of  small  quantities. 
The  milder  symptoms  may  arise  from  its  therapeutic  use,  but  typical 
cases  are  generally  due  to  the  presence  of  arsenic  in  the  form  of  dyes 
in  wall  paper  or  clothes,  or  in  stuffed  animals  in  the  rooms  inhabited 
by  the  victims,  or  to  the  constant  handling  of  arsenical  pigments  and 
other  compounds  in  mines  and  manufactories.  Widespread  poisoning 
has  been  observed  from  the  use  of  wines  containing  arsenic  at  Plyeres 
in  France,  from  milk  diluted  with  arsenical  water  in  London,  and 
from  beer  in  the  ^Manchester  district.  In  these  last  cases  the  arsenic 
was  in  solution,  but  it  often  seems  to  be  inhaled  in  the  form  of  fine 
dust,  which  falls  from  the  walls  or  other  objects.  It  has  been  sug- 
gested that  the  arsenic  dyes  are  decomposed  by  microbes  and  the 
volatile  arseniuretted  hydrogen  (AsHs)  inhaled,  but  there  seems  no 
reason  to  suppose  that  this  is  the  case,  and  the  inhalation  of  fine 
particles  is  a  sufficient  exi)lanation. 

The  symptoms  of  chronic  arsenic  poisoning,  which  are  often  very 
obscure,  may  be  divided  into  three  phases.  In  the  first  of  these,  the 
patient  complahis  of  weakness  and  languor,  loss  of  appetite,  some 
nausea  and  occasionally  vomiting,  with  a  sense  of  heaviness  and  dis- 
comfort in  the  stomach.  Diarrhoea  may  be  present,  but  is  often 
absent,  and  in  fact  some  constipation  may  occur. 

In  the  second  phase  the  conjunctiva  is  often  red  and  inflamed,  and 
symptoms  of  coryza  appear,  with  sneezing,  hoarseness  and  coughing, 
from  a  catarrhal  condition  of  the  mucous  membranes  of  the  nose  and 
larynx.  Some  swelling  of  the  liver  and  jaundice  may  occur,  but  these 
are  not  generally  well  marked.  Skin  eruptions  of  various  forms — 
papular,  vesicvilar,  or  erythematous — are  generally  noted;  very  often 
the  epidermis  falls  oft'  in  fine  brownish  scales,  or,  in  the  hands  and  feet, 
in  large  flakes  (keratosis);  a  curious  pigmentation  is  very  common, 
the  skin  assuming  a  dark  metallic  color  resembling  in  extreme  forms 
that  produced  by  rubbing  a  lead  pencil  upon  it  (arsenic  melanosis). 
This  pigmentation  is  much  more  marked  in  persons  of  dark  com- 
plexion than  in  fair  peojile,  in  whom  it  may  be  indistinguishable  from 
ordinary  freckles;  it  generally  disappears  when  the  patient  is  removed 
from  the  poisonous  atmosphere,  but  has  been  permanent  in  some  cases. 
In  prolonged  poisoning  the  eruptions  may  simulate  almost  any  form 
of  skin  disease,  and  the  hair  and  nails  fall  off.  Herpes  is  not  infre- 
quently observed  and  points  to  iiervous  disturbances  such  as  are 
prominent  features  in  the  next  phase. 


FAH)  sriiSTAXCKS   ACTlSd   M'TEli   ABSORPTION 

Tlicsr  ])li:isc's  are  not  always  distiuft  in  cases  of  poisoniiiu;,  aiifl  \ery 
often  some  of  the  symptoms  of  the  second  phase  may  appear  before 
any  marked  disorder  of  the  digestive  tract.  In  the  prohmged  thera- 
l)eutic  use  of  arsenic,  the  first  indications  of  commencing  poisoning 
are  rechiess,  suf^'usion  and  swelling  of  the  conjunctiva  and  eyelids, 
and  dryness  of  the  nose  and  throat,  as  in  coryza.  On  the  other  hand, 
in  workmen  exposed  to  arsenical  dust,  the  first  symptoms  may  arise 
from  the  skin  or  from  bronchial  irritation. 

'']"'he  ihird  phase  is  marked  by  disturbance  of  sensation  and  motion 
ill  localized  areas,  generally  in  the  hands  and  feet  (peripheral  neuritis). 
It  is  often  ushered  in  by  intense  persistent  headache  or  l)y  acute  pain 
located  around  the  knee,  ankle  or  foot,  less  frequently  in  the  wrist 
and  hand.  The  patient  complains  of  formication  in  the  extremities, 
and  of  the  discomfort  caused  by  the  pressure  of  the  bed-clothes  on  the 
f(>et  and  legs.  The  palms  of  the  hands  and  the  soles  of  the  feet  are 
often  red,  swollen  and  extremely  sensitive  to  touch  (erythromelalgia), 
and  pressure  on  the  muscles  induces  the  most  intense  pain.  Later, 
sensory  paralysis  may  set  in,  especially  in  the  extremities,  and  the  less 
acute  sense  of  touch  in  the  feet  and  hands  induces  symptoms  resembling 
those  of  locomotor  ataxia.  The  sensitiveness  to  heat  and  cold  may  be 
exaggerated  or  dulled,  or  sometimes  heat  is  not  appreciated,  while  cold 
causes  intense  pain.  The  sense  of  pain  varies  in  different  cases,  in 
some  being  abnormally  acute,  in  others  deadened.  These  sensory 
disturbances  are  followed  in  severe  ])oisoning  by  motor  paralysis,  which 
generally  appears  in  the  extensor  muscles  of  the  toes,  later  in  the  peronei 
muscles.  ^lore  rarely  the  flexor  muscles  of  the  leg  and  foot  are  in^•olved, 
and  in  some  cases  the  affection  commences  in  the  extensors  of  the  hand 
and  fingers.  As  a  general  rule  the  paralysis  is  confined  to  the  extremities, 
l)ut  in  some  cases  it  has  been  found  to  invade  tJie  trunk.  It  is  generally, 
l)ut  not  iinariably,  symmetrical,  and  the  muscles  affected  atrophy 
rapidly,  and  present  the  reaction  of  degeneration.  There  is  sometimes 
some  difficulty  experienced  in  diagnosing  arsenic  from  lead  paralysis, 
but  in  the  former  there  is  often  a  history  of  acute  poisoning,  while  the 
latter  is  almost  invarial)ly  due  to  ])rol()ngc(l  absor])tion.  Disturbances 
of  sensation  are  much  more  common  in  arsenic  than  in  lead  palsy,  and 
in  the  latter  the  forearm  miuscles  are  generally  affected  first,  in  the 
former  those  of  the  leg.  In  arsenic  ])oisoning  atrophy  is  said  to  occur 
iiiiich  more  rapidly,  and  there  is  no  line  on  the  giuns.  Another  condition 
w  liicli  i)rcscnts  still  greater  difficulties  in  diagnosis  is  alcoholic  neuritis. 
l}ut  ill  the  latter  skin  eruptions  are  extremely  rare,  coryza  is  not  present, 
and  there  are  generally  more  marked  brain  symj^toms  than  in  arsenical 
cases.  In  doubtful  cases  the  urine  and  the  hair  of  the  jvitient  should 
be  tested  for  arsenic. 

Arsenic  paralysis  may  a])])ear  as  early  as  three  days  after  an  acute 
intoxication,  but  is  commonly  obser\ed  later,  and  may  occur  only  after 
'.i-4  weeks. 

In  \-ery  prolonged  arsenic  poisoning  the  ])aticut  may  sink  into  an 
ajiathetic,  scini-idiotic  condition,  or  may  become  epilejitic.     In  most 


ARSENIC  591 

cases  the  symptoms  slowly  (lisa|)])t'iir  when  the  |)ois()ii  is  removed,  l)iit 
even  slight  paralysis  may  last  for  many  years  before  it  is  entirely  enr(><l, 
and  after  complete  degeneration  of  the  mnscles  little  impro\ement 
is  to  be  expected.  The  contractures  which  follow  are  generally  due  to 
the  uno])posed  action  of  the  sound  muscles,  but  sometimes  arise  from 
the  shortening  of  the  })aralyzed  ones. 

Therapeutic  Doses  of  arsenic  often  improve  the  api)etite  and  digestion 
and  there  is  good  reason  to  credit  its  prolonged  administration  with 
increasing  the  assimilation  of  the  food  and  retarding  the  tissue  waste; 
this  leads  to  acceleration  of  growth  and  increase  in  weight.  An  improved 
nutrition  of  the  skin  and  some  alteration  in  the  blood  cells  is  generally 
believed  to  arise  from  the  use  of  arsenic  in  quantities  too  small  to 
induce  chronic  poisoning. 

Action. — Arsenites  and  arsenious  acid  do  not  coagulate  proteins  or 
change  them  in  any  way,  except  when  ap])lied  in  such  enormous  quan- 
tities as  never  reach  the  stomach,  so  that  the  action  of  arsenic  on  the 
Alimentary  Canal  cannot  be  explained  as  due  to  any  ordinary  form  of 
corrosion,  although  the  symptoms  and  the  post-mortem  appearances 
reseml)le  in  many  points  those  of  the  corrosive  poisons.  Thus  the 
mucous  membrane  of  the  stomach  is  generally  found  red  and  swollen, 
and  often  contains  haemorrhages.  The  epithelial  coat  can  be  rul)bed 
off  very  easily,  and  is  found  to  be  in  a  state  of  fatty  infiltration,  and 
sometimes  resembles  a  false  membrane.  In  some  cases  no  congestion 
of  the  stomach  is  met,  the  only  lesion  consisting  in  cloudy  swelling  and 
fatty  infiltration  of  the  gland-cells,  similar  to  that  mentioned  under 
phosphorus. 

The  intestine  presents  very  similar  api)earances,  the  mucous  mem- 
brane being  swollen  and  congested,  more  esijccially  around  Peyer's 
patches.  It  contains  a  (juantity  of  thin  fluid  with  flakes  of  membrane, 
reseml)ling  exactly  the  rice-water  stools  of  cholera,  and  in  fact  it  may 
be  difficult  to  distinguish  the  intestine  of  arsenic  poisoning  from  that 
of  cholera. 

The  same  symptoms  arise  when  arsenic  is  a})sorbed  from  the  sub- 
cutaneous tissue,  or  from  the  broken  skin,  though  only  traces  of  arsenic 
are  found  in  the  contents  of  the  stomach  and  intestine  when  it  is  injected 
in  this  way. 

The  failure  to  explain  the  gastro-intestinal  action  of  arsenic  by  ordi- 
nary corrosion  has  led  to  the  suggestion  that  it  is  due  to  the  extreme 
dilatation  of  the  intestinal  vessels,  which  gives  rise  to  the  congestion 
and  swelling,  and  this  in  turn  to  the  destruction  of  the  lining  meml)rane, 
perhaps  by  the  exudation  of  fluid  beneath  the  epithelium.  This  trans- 
udation of  fluid  is  certainly  in  accord  with  the  watery  character  of  the 
stools  in  arsenic  poisoning,  but  the  explanation  does  not  seem  entirely 
satisfactory,  for  it  fails  to  account  for  the  fatty  infiltration  and  the 
cloudy  swelling  of  the  epithelimu,  which  are  in  some  cases  the  only 
lesions  found  here.  The  fatty  infiltration  is  not  confined  to  the  stomach 
and  bowel,  but  involves  a  number  of  other  organs,  although  it  is  not  as 
a  general  rule  so  widely  distributed  as  in  phosphorus  poisoning.    Arsenic 


:>\)2  SUliSTANCES   ACTINC  AFTER  ABSORPTION 

then  must  1)C  considorcd  to  liave  a  specific  action  in  causiiijj  fatty 
iiiiiltratioii  of  the  epithelium  of  the  stomach  and  intestine.  This  in 
itself  is  sufficient  to  explain  many  of  the  symptoms  from  these  organs, 
although  it  may  well  be  that  the  vascular  action  is  the  cause  of  the 
excess  of  fluid  in  the  intestine,  and  in  fact,  the  fatty  infiltration  alone 
is  insufficient  to  explain  this  feature,  which  is  absent  in  phosphorus 
]>oisoning.  In  cases  of  poisoning  where  the  arsenic  is  taken  by  the 
mouth,  and  especially  when  large  quantities  of  dry  arsenious  acid  are 
swallowed,  the  specific  action  on  the  epithelium  and  the  vascular 
action  are  ])robal)Iy  intensified  by  the  direct  contact  of  the  poison. 

In  therai)eutic  doses  arsenic  is  said  to  increase  the  appetite  and 
promote  digestion,  an  effect  which  may  perhaps  be  due  to  the  specific 
action  on  the  epithelium,  this  in  its  milder  forms  proving  of  advantage 
to  the  organ,  though  in  excess  it  leads  to  its  degeneration;  and  it  has 
been  obser\ed  in  dogs  with  gastric  fistidte  that  the  gastric  secretion  is 
augmented  by  small  quantities  of  arsenic. 

Circulation. — In  the  frog  the  heart  is  slow,  weak,  and  irregular,  and 
ceases  in  diastole  after  comparatively  small  doses;  the  action  seems  to  be 
a  direct  paralysis  of  the  nuiscle.  In  the  mammal  the  heart  is  little  affected 
by  arsenic,  but  a  Acry  marked  fall  of  the  blood  pressure  follo^^■s  the 
injection  of  large  doses  intravenously.  This  is  due  to  dilatation  of  the 
arterioles  and  capillaries  from  a  direct  action  on  tlie  muscular  coat; 
adrenaline  and  nicotine  continue  to  contract  the  vessels  after  arsenic, 
because  though  the  muscle  is  weak  it  can  still  respond  to  strong  nervous 
im])ulses;  the  vessels  of  the  splanchnic  areas  seem  more  susceptible 
to  this  arsenic  action  than  those  of  the  rest  of  the  body,  and  their 
dilatation  leads  to  very  marked  congestion  of  the  stomach  and  bowel, 
and  reduces  the  blood-pressure  to  zero.  Some  evidence  has  been  l)rought 
forward  that  under  arsenic  the  capillaries  permit  the  passage  of  fluid 
into  the  tissues  more  readily  tlian  normally;;  this  may  ex])lain  the 
appearance  of  oedema  in  cases  of  poisoning  and  also  the  large  amoimt 
of  fluid  in  the  stools  and  vomited  matter.  Arsenic  is  therefore  often 
termed  a  capillary  poison. 

Respiration. —  In  cases  of  poisoning  in  man  the  res])iration  does 
not  seem  to  lie  much  affected  until  late,  but  it  ceases  before  the  heart, 
])rol)ably  from  the  exhaustion  and  low  blood-pressure,  and  nt)t  from 
any  specific  action  on  the  centre. 

The  action  of  arsenic  on  the  Central  Nervous  System  has  been  re- 
peatedly- examined.  A  descending  ])aralysis  is  elicited  in  the  frog,  the 
animal  first  losing  its  spontaneous  mo\ements,  and  then  its  reflexes, 
and  the  terminations  of  the  motor  nerves  being  involved  only  very 
late  in  the  intoxication.  In  mammals  there  are  generally  no  certain 
indications  of  direct  action  on  the  ner\ous  s>stem  in  acute  jioisoning, 
for  the  weakness  and  jirostration,  and  the  final  loss  of  consciousness 
and  coma  may  be  attril)uted  to  the  exhaustion  from  the  gastro-intestinal 
effects  rather  than  to  the  centres  being  immediately  affected. 

'^I'he  ])athology  of  the  nervous  disturl)ances  observed  in  chronic 
|)()isoning,  and  often  after  a  single  large  but  not  unmediately  fatal 


ARSENIC 


593 


(lose,  boars  no  relation  to  the  etVeets  ol)serve(l  in  aiiiinals  in  aeute 
poisoning.  The  symi)tonis  in  ehronie  jjoisoning  all  point  to  i)erii)heral 
neuritis  as  the  cause,  and  the  characteristic  lesions  in  the  ner\e  trunks 
have  been  shown  to  occur  both  in  man  and  animals  exposed  to  the 
prolonged  action  of  arsenic.  In  severe  cases  the  spinal  cord  may  also 
be  involved  secondarily.  The  peripheral  muscles  and  nerves  are  little 
affected  in  acute  poisoning. 

The  unbroken  Skin  is  not  affected  by  arsenic,  unless  when  it  is  ai)plied 
repeatedly  or  allowed  to  remain  in  contact  with  it  for  some  time,  when 
it  may  give  rise  to  redness,  pustules  or  vesicles  and  later  to  violent 
erysipelatoid  inflammation.  It  has  not,  however,  any  such  corrosive 
action  on  the  skin  as  is  possessed  by  strong  acids,  and  the  subcuta^neous 
injection  of  arsenic  is  not  painful.  It  is  more  active  when  applied  to 
denuded  surfaces  and  to  the  mucous  membranes,  destroying  them  to 
some  depth  and  causing  acute  pain,  but  even  here  it  acts  more  slowly 
than  ordinary  caustics.  It  seems  to  act  only  upon  living  cells,  and 
unlike  acids  and  alkalies,  forms  no  combinations  with  the  dead  tissues. 
The  local  effects  of  arsenic  on  the  skin  are  seen  only  in  workmen  handling 
arsenic,  as  in  color  factories,  in  which  affections  of  the  skin  of  the  face, 
hands  and  scrotum  are  by  no  means  rare. 

In  arsenic  poisoning  skin  eruptions  are  common,  and  may  be  due 
in  part  to  circulatory  disorders,  but  are  to  be  ascribed  for  the  most 
part  to  the  direct  action  of  the  drug  on  the  skin.  This  appears  to 
accelerate  the  growth  and  proliferation  of  the  epithelium,  which  is 
found  to  be  increased  in  thickness,  but  which  in  very  severe  cases 
shows  signs  of  atrophy  and  degeneration.  Arsenic  has  been  found  in 
appreciable  amount  in  the  hair  and  ei)idermal  scales,  and  in  the  fluid 
of  a  blister  in  patients  treated  with  it,  and  changes  in  the  condition  of 
the  skin  in  animals  have  also  been  observed. 

The  melanosis  of  arsenic  poisoning  seems  to  be  due  to  the  deposition 
not  of  an  arsenical  compound,  but  of  some  organic  product  in  the  deeper 
layers  of  the  corium.  The  symptoms  of  irritation  of  the  mucous  mem- 
branes of  the  eye,  nose  and  larynx  are  analogous  to  the  skin  eruptions. 

The  action  of  arsenic  on  The  Blood  is  still  obscure,  although  it  is 
frequently  prescribed  in  various  forms  of  ansemia.  In  chlorosis  and 
in  normal  persons,  it  is  said  to  diminish  the  number  of  the^  red  cor- 
puscles, but  not  to  alter  the  total  hiemoglobin  of  the  blood.  Stockman 
and  Greig  found  the  blood  cells  and  ha?moglobin  unaltered  by  arsenic 
in  normal  animals,  but  describe  the  bone-marrow  as  evidently  in  a 
state  of  unusual  activity,  indicated  by  its  increased  ^•ascularity,  greater 
number  of  red-blood  corpuscles  and  lessened  fat  cells.  In  a  case  of 
pernicious  ana?mia  recently  examined  by  Engel,  it  was  found  that 
arsenic  increased  the  number  of  young  newly  formed  red  cells  while  the 
number  of  more  mature  corpuscles  was  diminished.  Bettman  states 
that  in  subacute  poisoning  in  ra})bits,  the  red  cells  and  hivnioglobin 
are  diminished,  and  nucleated  red  cells  appear  in  the  blood  in  some 
number;  and  from  this  it  has  been  suggested  that  arsenic  may  accelerate 
the  destruction  of  the  blood  cells  and  thus  induce  a  more  rapid  formation 
38 


594  SCHST.WCES   ACTING  AFTER  ABSORPTION 

imlinrtly  as  ti  sort  of  <(>m])('Msati()n;  but  there  is  no  evidence  tliat  thera- 
j)eutic  (loses  increase  tlie  destruction  of  the  blood  cells  and  this  view 
may  l)e  dismissed  as  fanciful,  (nmn  has  shown  that  in  shed  blood 
small  quantities  of  arsenite  protect  the  red  cells  from  various  hemolytic 
agents  and  suggests  that  this  may  occur  in  the  therapeutic  use  of 
arscMiic.  After  hamiorrhage  the  blood  is  said  to  regenerate  more 
(juickly  if  arsenic  is  given,  and  the  number  of  red  cells  rises  faster  than 
the  lijciiioglobin. 

The  Metabolism  is  affected  })y  a  poisonous  dose  of  arsenic  in  the 
same  way  as  by  phosphorus,  but  the  alteration  is  not  generally  so 
marked  and  is  lial)le  to  be  overlooked,  owing  to  the  more  intense  action 
on  the  alimentary  canal.  The  nitrogen  of  the  urine  is  considerably 
greater  than  that  of  inanition,  Init  it  is  not  quite  clear  whether  this  is 
due  to  an  increase  in  the  urea  or  to  other  nitrogenous  substances.  The 
annnonia  is  probably  augmented,  for  a  considerable  amount  of  lactic 
acid  has  been  obtained  from  the  urine.  The  glycogen  of  the  liver 
disappears  entirely,  and  the  liver  seems  incapable  of  forming  it  from  the 
sugar  of  the  food;  yet  it  is  said  that  imder  arsenic  treatment  quantities 
of  sugar  can  be  assimilated,  which  would  normally  be  sufficient  to  cause 
glycosuria.  Lesion  of  the  medulla  oblongata  (diabetes  puncture)  does 
not  cause  glycosuria  after  arsenic,  but  curara  and  other  drugs  are  still 
capable  of  eliciting  this  symptom.  The  fatty  degeneration  of  the  epithe- 
lium of  the  stomach  and  intestine  has  been  mentioned  already,  but  this 
alteration  is  not  confined  to  these  tissues,  being  found  in  the  liver  and 
kidney,  in  the  muscle  cells  of  the  heart,  bloodvessels  and  striated  muscles, 
and  in  the  lining  epithelium  of  the  alveoli  of  the  lungs.  Small  necrotic 
foci  hiixe  been  observed  by  Wolkow  in  the  liver,  along  with  signs  of 
active  division  of  the  parenchymatous  cells,  as  in  phosphorus  poisoning. 
The  catalase  of  the  blood  and  tissues  is  said  to  be  increased  by  thera- 
peutic doses  in  poorly  nourished  animals,  while  this  change  does  not 
occur  in  strong  and  healthy  indi\iduals. 

The  changes  in  the  metabolism  under  arsenic  resemble  those  under 
phosphorus,  so  that  they  have  generally  been  regarded  as  arising  from 
a  similar  action.  The  action  on  the  autolytic  ferment  was  said  to  be 
diametrically  ojjposite,  but  it  ap])ears  that  small  quantities  of  arsenic, 
corresponding  to  those  causing  chronic  poisoning,  accelerate  autolysis 
in  the  same  way  as  phosphorus;  very  large  amoinits  may  arrest  the 
autolysis  by  destroying  the  ferment.  But  arsenic  in  small  doses  has 
much  less  influence  on  the  tissue  change  than  phos])liorus. 

'J'lie  fatty  infiltration  may  \vd\e  the  same  results  as  in  phosphorus 
poisoning.  The  liver  is  somewhat  enlarged  and  the  pressure  on  the 
bile  ducts  ])revents  the  escape  of  bile  into  the  intestine,  and  thus 
induces  jaimdice  and  the  appearance  of  bile  pigments  and  bile  acids 
in  the  uritie.  Jaundice  is  seldom,  however,  a  very  marked  feature  in 
ansenic  ])ois(>ning,  and  is  often  entirely  absent.  The  bile  is  said  to 
contain  albumin,  red-blood  cells,  and  casts,  as  in  ])hosphorus  ])oisoning, 
but  does  not  present  other  changes  except  immediately  before  death. 

The  prolonged  administration   of  arsenic  in  quantities  insufHcient 


ARSENIC  595 

to  produce  chroiiic  ])oisoiiiii<;'  is  reiHitod  to  have  some  effect  on  tlie 
Growth  and  Nutrition.  It  is  difficult  to  obtain  accurate  data  in  rej^jard 
to  this  ])oiiit,  and  while  the  improvement  in  nutrition  is  attested  l)y  a 
number  of  independent  observers,  other  equally  careful  investigators 
have  not  been  able  to  confirm  their  results.  Gics  treated  some  of  a 
litter  of  young  rabbits  with  arsenic  in  minute  doses  for  several  weeks, 
and  found  that  they  weighed  more,  and  were  larger  in  every  way  than 
the  untreated  animals;  the  subcutaneous  fat  was  much  greater  in 
amount,  the  bones  were  longer,  and  the  muscles  more  developed.  The 
long  bones  presented  the  appearance  described  by  Wegner  under  ])hos- 
phorus  treatment,  being  longer  and  containing  more  dense  bone  both 
in  the  shaft  and  the  epiphyses.  Female  rabbits  treated  with  arsenic 
l)ore  young  of  abnormal  size  and  weight.  Several  other  observers  have 
described  a  more  rapid  growth  and  greater  activity  in  young  animals 
treated  with  arsenic,  and  an  increase  in  weight  is  often  noted  in  man. 
On  the  other  hand  Stockman  and  Greig  observed  no  change  in  the 
growth  of  animals  under  prolonged  treatment  with  arsenic,  and  found 
that  the  only  tissues  affected  were  the  growing  bones,  which  appeared 
denser  than  usual. 

The  improvement  in  nutrition  has  not  been  explained,  though  a 
slight  decrease  in  the  nitrogenous  excretion  and  in  the  amount  of 
nitrogen  in  the  stools  has  been  noted  by  Weiske,  who  holds  that  more 
of  the  food  is  utilized  by  the  digestive  apparatus,  and  at  the  same 
time,  less  protein  is  decomposed  in  the  tissues.  The  change  in  the 
amount  of  nitrogen  excreted  is  so  small,  however,  that  doubt  may  be 
entertained  whether  it  may  not  be  due  to  unavoidable  errors  in  the 
estimation,  and  other  investigators  have  been  unable  to  detect  any 
alteration  attributable  to  the  drug.  Fresh  investigation  of  this  point 
is  thus  required  before  certainty  can  be  reached  regarding  the  effects 
on  the  nutrition,  and  still  more  regarding  the  explanation  of  the  altera- 
tions. 

When  small  quantities  of  arsenic  are  taken  habituall}'.  Tolerance 
is  established,  and  the  dose  may  be  gradually  increased  until  it  far 
exceeds  that  which  would  be  poisonous  in  ordinary  persons.  This  is 
the  explanation  of  arsenic-eating  which  is  known  to  exist  in  different 
parts  of  the  world,  but  which  is  most  widespread  and  best  known  in 
Styria  and  the  Tyrol.  The  peasants  there  indulge  in  the  poison  habit- 
ually, and  l)elieve  that  it  enables  them  to  work  better,  and  in  par- 
ticular to  climb  the  mountains  with  less  effort  and  less  respiratory 
distress.  They  also  credit  it  with  improving  their  complexions  and 
general  appearance,  and  give  it  to  their  horses  in  order  to  render  their 
coats  more  smooth  and  glossy,  and  to  make  them  stronger  and  fatter. 
Knapp  administered  0.4  G.  (7  grs.)  of  arsenious  acid  to  one  of  the 
peasants  at  Graz  without  inducing  any  effects  whatsoever.  Arsenic- 
eating  is  said  to  be  indulged  in  to  a  considerable  extent  by  young  women 
in  some  countries  with  the  object  of  improving  the  complexion  and 
figure,  and  cases  of  arsenic  habit  have  been  described  in  different  parts 
of  America  and  elsewhere.    As  far  as  can  be  observed,  the  habit  is  not 


')0G  sriiSTANCES   ACTING   AFTER   ABSORPTION 

(Iclrtcrioiis,  for  the  Styriaii  peasants  live  to  old  age,  and  no  symptoms 
attrihiitahle  to  the  poison  have  been  noted.  As  a  general  rnle  large 
doses  are  taken  onee  or  twiee  a  week,  and  no  fluid  is  swallowed  for  some 
time  afterward. 

C'loetta  treated  animals  in  this  way  with  dry  arsenic  and  sueeeeded 
in  obtaining  tolerance  of  large  doses;  at  first  a  considerable  ])r()i)or.tion 
was  absorbed  and  excreted  in  the  urine,  but  as  the  treatment  con- 
tinued, less  appeared  in  the  urine  and  more  in  the  stools.  An  animal 
that  was  not  injured  by  large  quantities  given  by  the  mouth,  suc- 
cumbed to  quite  small  doses  administered  hypodermically.  He  hokls 
that  the  tolerance  to  arsenic  arises  from  the  intestine  failing  to  absorl) 
the  ])oison,  and  believes  that  no  tolerance  is  attained  when  arsenic  is 
injected  hypodermically.  But  considerable  amounts  of  arsenic  have 
been  obtained  from  the  urine  of  arsenic-eaters,  which  shows  that  in 
these  peojile  the  tolerance  is  not  due  to  non-absor])tion. 

As  a  contrast  to  the  Styrian  peasants,  the  miners  of  Reichenstein 
may  be  mentioned,  who  are  constantly  exposed  to  arsenic  owing  to 
its  being  contained  in  large  quantities  in  the  ore.  These  people  are 
described  by  Geyer  as  shortlived,  \ev\  subject  in  childhood  to  se^•ere 
rickets  and  in  adult  life  to  dropsies  and  respiratory  diseases;  they 
offer  little  resistance  to  microbial  infection  and  frequently  present  the 
skin  and  nervous  symptoms  of  arsenic  poisoning.  The  difference  in 
the  reactions  of  these  peoples  may  arise  in  part  from  differences  in  the 
general  nutrition,  for  Delepine  and  others  have  found  that  animals 
supplied  with  abimdant  food  and  in  good  hygienic  conditions  sur^•i^'e 
under  chronic  arsenic  poisoning  much  longer  than  less  well  nourished 
ones.  This  difference  in  the  nutrition  may  also  explain  the  fact  that  in 
epidemic  })oisoning,  as  in  the  ]\Ianchester  cases,  comparatively  few  of 
the  ])ersons  ex])()sed  to  the  poison  exhibited  any  sym])toms  from  it. 

Arsenic  is  Excreted  very  slowly,  some  a])})earing  in  the  urine  and 
fjeces  within  24  hours,  but  only  about  one-fifth  of  tliat  absorbed  being 
eliminated  in  this  way.  The  rest  is  stored  in  the  tissues  for  a  long 
time  and  slowly  got  rid  of  in  the  hair  and  c])idermis,  in  which  arsenic 
may  be  found  for  many  mcmths  after  it  has  disappeared  from  the 
urine  and  fax-es.  Traces  may  be  found  in  other  secretions,  and  fatal 
intoxication  has  been  observed  in  a  child  from  the  milk  of  its  mother, 
who  was  suffering  from  acute  i)oisoning.  In  the  urine  arsenic  api)ears 
in  ])art  in  organic  combinations.  It  is  probable  that  the  elVects,  esjiecially 
the  i)aralysis,  last  long  after  the  drug  Jias  been  excreted,  lesions  ha\ing 
been  inducetl  which  only  recover  slowly. 

Arsenic  disappears  rapidly  from  the  blood  when  injected,  being 
taken  u])  by  the  tissues  in  which  it  forms  firm  combinations  with  the 
nuclcins;  it  is  foimd  chieHy  in  tlie  li\er,  and  is  also  deposited  in  the 
kidney,  in  the  walls  of  the  stomach  and  intestine,  and  in  the  si)lecn 
and  hnigs.  Much  smalliT  cpiantities  are  found  in  the  muscles  and  in 
ihc  ncrxdus  tissues,  in  which  it  is  said  to  occur  in  larger  ])ro])ortion 
in  the  white  than  in  the  gra\'  matter.  It  has  been  detected  in  the 
caneellons  bones  of  the  skull  and  vertebra*,  after  it  Jiad  disappeared 
from  all  the  otiier  organs. 


ARSENIC  '"^^^ 

Arsenic  is  poisonous  to  many  of  the  lower  forms  of  life,  as  well  as  t^  the 
vertebrates;  thus  it  has  l)een  found  that  its  presence  in  comparatively  dilute 
solution  (one  part  of  arsenious  acid  in  30,(100  parts  of  water)  hinders  the  develop- 
ment of,  and  event uallv  kills,  alj!;a'  and  the  seeds  of  the  higher  plants.  On  the 
other  hand,  moulds  grow  aljundantly  in  a  solution  of  potassium  arsemtc  (1  per 
cent.)  containing  some  organic  matter,  and  the  alcoholic  fermentation  proceeds 
in  the  presence  of  arsenic,  although  it  is  somewhat  retarded  at  first;  very 
dilute  solutions  of  arsenic  even  accelerate  the  fermentation,  as  is  true  of  most 
other  antiseptics.  Arsenious  acid  is  only  about  one-tenth  as  strong  an  antiseptic 
as  perchloride  of  mercury,  and  the  spores  of  anthrax  are  destroyed  only  after 
ten  davs  in  a  one  per-mille  solution.  It  has  therefore  a  greater  antiseptic  power 
than  manv  of  the  other  acids,  but  compared  with  its  action  on  the  higher  forms 
of  life,  it  is  but  slightly  poisonous  to  the  fungi.  It  seems  to  have  no  effect  on  the 
activity  of  the  ferments,  such  as  pepsin,  myrosin,  and  emulsin.  Some  patho- 
genic protozoa  are  extraordinarily  susceptible  to  the  action  of  arsenic;  thus  a 
concentration  of  arsenic  in  the  blood  of  1  in  200,000  is  sufficient  to  destroy 
manv  of  the  trvpanosomes,  while  other  protozoa  living  in  water  may  survive 
in  a  1  in  5,000  solution.  All  the  parasitic  protozoa  are  not  so  readily  destroyed, 
howe\-er,  for  that  of  malaria  is  found  to  be  much  more  resistant.  When  an 
animal  infected  with  trvpanosomes  is  treated  ^^^th  arsenic,  the  parasites  often 
disappear  from  the  blood  for  some  days  or  weeks  and  then  reappear,  but  can 
again  be  expelled  by  arsenic,  though  for  a  shorter  tune;  this  phenomenon  of 
developed  tolerance  is  better  known  when  these  organisms  are  treated  with 
organic  arsenic  compounds  and  will  be  discussed  there  (p.  603).  Apparently 
infusoria  also  acquire  a  certain  tolerance  of  arsenic  and  other  metallic  poisons 
in  water,  but  the  very  high  resistance  seen  in  the  trypanosomes  in  the  blood  has 
not  been  observed  in  these  non-parasitic  protozoa. 

The  arsenates  are  much  less  harmful  to  lowly  organized  forms,  for  seeds 
and  alga?  as  well  as  moulds  grow  in  a  neutral  solution  abundantly,  and  even 
the  infusoria  do  not  seem  injured  by  it  to  any  marked  degree.  Apparently 
these  plants  and  animals  are  incapalDle  of  reducing  the  arsenates  to  arsenites, 
wliich  are  much  more  toxic. 

The  bodies  of  persons  poisoned  with  arsenic  are  said  to  remam  undecom- 
posed  for  a  remarkably  long  time,  and  to  tend  to  become  mummified.  The 
statement  is  still  disputed,  but  is  vouched  for  by  a  number  of  authorities. 
It  is  certainly  not  invariably  the  case,  and  little  weight  is  to  be  laid  upon  mum- 
mification in  determining  whether  arsenic  poisoning  was  the  cause  of  death  in 
exhumed  persons. 

No  account  of  the  pharmacology  of  arsenic  would  be  complete  without 
mention  of  the  theory  advanced  by  Binz  and  Schulz  to  explain  its  action. 
They  suppose  that  arsenious  acid  is  oxidized  to  arsenic  acid  by  the  living  tissues, 
and  the  arsenic  acid  again  reduced  to  arsenious.  In  this  way  oxygen  is  alter- 
natelv  withdrawn  from  and  supplied  to  the  protoplasm,  and  this  alternate 
reduction  and  oxidation  they  suppose  to  be  the  essential  feature  of  the  action 
of  arsenic.  The  grounds  on  which  this  explanation  is  based  must  be  sought 
in  the  numerous  papers  on  the  subject  by  these  authors,  and  it  may  suffice 
here  to  state  that  while  arsenic  acid  appears  to  be  reduced  and  arsenious  acid 
oxidized  in  the  tissues,  these  processes  are  probably  only  gradual.  Otherwise 
it  would  be  difficult  to  explain  how  arsenious  acid  is  so  much  more  poisonous 
than  arsenic  acid,  for  if  the  latter  were  readily  reduced  to  arsenious  acid  it 
would  be  eciually  toxic. 

Arsenic  and  phosphorus  are  inchided  in  one  group  in  chemistry, 
and  their  effects  on  living  organisms  present  sufficient  resemblance 
to  justih-  their  association  in  the  pharmacological  system.  The  mucous 
mem])ranes  and  the  skin  are  more  afl'ected  by  arsenic,  howe\-er,  and  the 
circulation  is  more  rapidly  depressed,  while  the  fatty  infiltration  is 
much  more  prominent  in  phosphorus  poisoning.  The  differences  between 


59S  SUBSTANCES  ACTING  AFTER  ABSORPTION 

their  eft'ects  are  more  in  degree  than  in  kind,  and  tliere  seems  no 
question  that  their  ultimate  action  on  protoplasm  is  of  the  same  nature. 
It  is  to  be  noted,  however,  that  there  is  no  reason  to  suppose  that 
phosphorus  o\\es  its  action  to  any  of  its  numerous  compoimds  with 
oxygen,  while  it  is  probable  that  the  oxides  of  arsenic  alone  are  capable 
of  modifying  vital  functions. 

The  Sulphur  Compounds  of  arsenic  are  entirely  insoluble  and  are  therefore 
not  absorbed  as  sucli,  but  it  seems  likely  that  small  quantities  of  arsenious 
acid  are  formed  from  them  in  the  intestine;  by  microbes.  Commcrc'ial  orpiment 
often  contains  hu'^e  amounts  of  arsenious  acid. 

Arseniuretted  Hydrogen  (AsHs)  is  an  exceedingly  poisonous  gas,  which 
has  caused  a  nuinl)er  of  fatal  accidents  from  being  inhaled  acciclentally  in 
chemical  laboratories.  Its  action  is  cjuite  different  from  that  of  the  oxides  of 
arsenic  and  there  is  no  reason  to  suppose  that  arsenites  give  rise  to  apprcciat:)le 
amoimts  of  the  gas  in  the  body,  or  that  the  effects  of  the  latter  arise  from  the 
formation  of  arsenites.  Its  action  arises  from  its  great  affinity  for  haemoglobin, 
which  takes  it  up  in  large  cjuantity  and  combines  with  it  or  with  some  product 
derived  from  it.  This  leads  to  hsemolysis,  and  the  haemoglobin  liberated  induces 
severe  symptoms  in  the  course  of  its  excretion.  In  the  test-tube  arseniuretted 
hydrogen  forms  a  combination  with  haemoglobin  which  gives  a  characteristic 
spectrum,  but  this  has  not  been  shown  to  occur  in  living  animals.  Most  of  the 
symptoms  appear  to  arise  from  the  haemolj^sis,  but  there  may  be  in  addition 
some  direct  action  on  the  central  nervous  system. 

Ai'seniurctted  hydrogen  induces  intense  headache,  nausea  and  vomiting, 
prostration  and  fainting  fits,  cyanosis  and  collapse.  Haemoglobin,  metha'mo- 
globiu,  luematin  and  occasionally  blood  are  passed  in  the  urine,  and  more  rarelj'' 
the  stools  contain  blood.  Sometimes  the  urine  is  entirely  suppressed  from  the 
tubules  being  plugged  with  blood  cells  and  debris,  and  intense  icterus  appears 
from  the  formation  of  excess  of  bile-pigment  from  tlie  haemoglobin  of  the 
disintegrated  corpuscles.  (Edema  of  the  lungs  or  sudden  failure  of  the  heart 
is  the  cause  of  death.  Some  of  the  gas  is  excreted  by  the  lungs,  and  may  be 
re(^ognized  by  its  garlic  odor,  and  some  arsenic  appears  in  the  urine,  but  it  is 
not  known  in  what  form.  It  is  estimated  that  one  part  in  100,000  parts  of  air 
is  injurious  to  man  if  breathed  for  a  few  hours. 

Preparations. 

AiiSENi  TiuoxmuM  (U.  S.  P.),  Acidum  Arseniosum  (B.  P.)  (AsaOa),  arsenous, 
or  arsenious,  acid  anhydride,  white  arsenic,  ratsbane,  forms  a  white  })()wder,  or 
opa<iue,  porcelain-like  masses,  or  a  transparent,  amorphous  surface  like  glass. 
It  dissoh'cs  slowly  in  cold  water,  the  glassy  variety  requiring  about  thirty,  the 
porcelain  about  eighty  parts  of  water.  It  is  almost  tasteless  antl  has  no  odor. 
2  mg.  (.j'„  gr.);  B.  P.,  ,;V~tit  gi'-,  in  pill  or  solution,  after  meals. 

Lujuor  Acidi  Arsenosi  (U.  S.  P.),  Liquor  Arsenici  Ilydrochloricu.^  (B.  P.),  a 
1  per  cent,  solution  of  arsenous  anhydride  acidulated  with  hydrochloric  acid. 
0.2  c.c.  (3  mins.);  B.  P.,  2-8  mins.,  3-5  drops  three  times  daily,  after  meals. 

LiQuou  PoTASsii  Arsknitis  (U.  S.  p.),  Liquor  Arsenicalis  (B.  P.),  Fowler's 
solution,  contains  1  per  cent,  of  arsenous  anhydride  rendered  alkaline  with 
bicarbonate  of  potash,  to  which  comi)ound  tincture  of  laventler  is  added  to  give 
color  and  flavor.  0.2  c.c.  (3  mins.);  B.  P.,  2-8  mins.,  3-5  drops  three  times 
daily,  after  meals. 

Sodii  Arscnas  (U.  S.  P.)  (Na2HAs04-t-7Il20)  forms  colorless,  odorless 
crystals,  very  soluble  in  water,  with  a  mild,  alkaline  taste.    5  mgs.  (,'„  gr.). 

Sudii  Arscnas  Anhydrosus  (B.  P.),  Sodii  Arstnns  Exsicadus  (U.  S.  P.) 
(NaJIAsO,),  is  pn'|)ar('d  from  the  ordinary  arsenate  (U.  S.  P.)  by  driving  off 
the  water  of  crysfaHizalion,  and  forms  a  white  jjowder.    3  mg.  (.,'„  gr.);   B.  P., 

4  0     lu    gl- 


Arsenic  599 

Liquor  Sodii  Arsenatis  (U.  S.  P.,  B.  P.),  Pearson's  solution,  a  1  per  cent, 
solution  of  dried  sodium  arsenate.     0.2  c.c.  (3  niins.);  B.  P.,  2-8  mins. 

Arseni  lodidum  (U.  S.  P.),  Arsenii  lodidum  (B.  P.)  (Asis),  glossy,  orange-red 
crystals  soluble  in  7  parts  of  water,  but  the  solution  soon  decomposes  into 
arsenous  and  hydriodic  acids.     5  mg.  (n,  gr.);  B.  P.,  urh  gr. 

Liquor  Arseni  (Arsenii,  B.  P.)  et  Hydrargyri  Iodidi  (U.  S.  P.,  B.  P.), 
Donovan's  solution,  contains  1  per  cent,  of  arsenic  iodide  and  1  per  cent,  of 
red  mercuric  iodide.  This  solution  is  clear  and  yellowish,  without  odor,  but 
with  a  harsh  metalhc  taste.    0.1  c.c.  (1|  mins.);  B.  P.,  5-20  mins.,  after  meals. 

Some  mineral  waters  contain  arsenic,  that  of  Levico  as  much  as  8  ings.  per 
litre. 

Therapeutic  Uses. — The  action  of  arsenic  as  ascertained  from  experi- 
ments on  the  lower  animals  and  from  cases  of  poisoning  in  man  throws 
little  light  on  its  nse  in  therapeutics,  and  so  little  is  known  of  the 
pathology  of  most  of  the  conditions  in  which  it  is  found  of  benefit, 
that  no  attempt  can  be  made  to  bring  the  two  series  of  observations 
into  relation.  The  treatment  of  trypanosoma  infections,  such  as 
sleeping  sickness,  with  arsenic  and  its  compounds  has  given  rise  to 
the  idea  that  man>'  of  the  conditions  in  whicli  arsenic  is  useful  may 
arise  from  protozoal  infection.  But  there  is  no  question  that  arsenic 
acts  in  other  ways  than  by  destroying  parasites,  and  such  speculation 
is  futile  until  the  cause  of  these  diseases  has  been  determined. 

Arsenious  acid  has  been  used  externally  as  a  caustic,  formerly  in 
various  forms  of  malignant  disease,  more  recently  in  lupus,  in  which 
it  is  said  to  destroy  the  diseased  surface  while  leaving  the  healthy  skin 
unaffected.  It  has  been  superseded,  however,  by  the  introduction  of 
surgical  measures,  such  as  scraping  with  the  sharp  spoon.  Arsenous 
anhydride  is  still  used  in  dentistry  to  destroy  the  pulp  in  decayed  teeth; 
this  destructive,  caustic  action  proceeds  more  slowly  than  under  more 
violent  corrosives,  so  that  there  is  little  or  no  pain  from  it. 

Internally  arsenic  is  used  in  malarial  disease,  especially  in  invet- 
erate cases  in  which  there  is  much  cachexia.  In  acute  cases  it  is  also 
of  benefit,  but  is  much  less  certain  in  its  effects  than  quinine;  it  may 
act  here  by  improving  the  general  nutrition  and  lessening  the  cachexia 
and  wasting,  but  in  addition  arsenic  acts  on  the  malarial  parasite, 
though  less  powerfully  than  quinine.  Many  authorities,  in  fact,  de- 
precate the  use  of  arsenic  in  acute  malaria,  and  would  limit  its  use 
to  the  cachexia  of  old  disease,  while  others  advise  its  use  with  iron  in 
ordinary  cases,  after  the  acute  stage  has  been  successfully  treated  with 
quinine.  In  obstinate  cases  it  is  probable  that  the  quinine  action  may  be 
reinforced  by  arsenic  and  that  parasites  which  have  a  low  susceptibility 
to  quinine  may  succumb  to  the  arsenic.  Thus  while  malaria  generally 
does  not  require  the  use  of  arsenic,  if  the  disease  does  not  yield  to 
quinine  carefully  administered  the  patient  may  be  treated  with  arsenic 
and  quinine  together. 

Arsenic  has  also  been  used  with  benefit  in  neuralgia,  especially 
when  it  assumes  a  periodic  character,  and  in  chronic  rheumatism,  but 
in  many  cases  no  definite  improvement  follows,  and  the  conditions 
under  which  it  is  of  value  cannot  be  more  accurately  defined  at  the 
present  time.    Old  cases  of  chorea  often  improve  under  arsenic,  which 


GOO       SUBSTANCES  ACTING  AFTER  ABSORPTION 

may  imply  some  action  on  the  central  nervous  system,  althoujj;h  as 
has  been  stated,  little  alteration  in  the  nervous  functions  is  observed 
ill  animals  excei)t  under  very  large  doses.  Asthma  has  also  been  treated 
with  arsenic  given  by  the  stomach,  or  by  the  inhalation  of  arsenic 
from  smoking  cigarettes  made  with  arsenical  paper. 

Small  doses  of  arsenic  are  often  of  service  in  increasing  the  appetite 
and  improving  the  general  condition  in  diseases  accomi)anied  by 
cachexia,  want  of  appetite,  general  weakness,  and  apathy. 

In  pernicious  anaemia,  arsenic  is  said  to  be  beneficial,  but  the  im- 
pro\ement  is  only  temporary.  ]\Iany  forms  of  skin  disease  are  treated 
with  arsenic,  some  of  them  with  the  hai)i)iest  results.  Thus  in  psoriasis, 
chronic  eczema,  and  lichen  ruber,  marked  improvement  or  complete 
recovery  often  dates  from  the  beginning  of  the  arsenic  treatment. 
It  is  generally  advised  only  in  the  chronic  forms,  and  is  said  to  be 
positively  deleterious  during  the  earlier  stages  of  rapid  cell  proliferation. 

In  lymphoma  arsenic  has  been  gi\-en  internally  and  also  by  direct 
injection  into  the  timiors,  and  often,  though  not  by  any  means  invari- 
ably, proves  of  value.  Various  other  forms  of  leuctemia  have  been 
treated  with  less  success. 

Arsenic  has  been  used  in  syphilis  in  combination  with  mercury  for 
over  a  century,  and  attention  has  again  been  drawn  to  this  action 
through  the  efficacy  of  its  new  organic  compounds,  For  this  purpose 
Donovan's  solution  of  the  iodides  of  arsenic  and  mercury  has  generally 
been  used.  The  quantity  of  iodide  present  in  this  solution  is  insufficient 
to  luue  any  specific  iodide  action  and  the  improvement  under  it  must 
thus  be  credited  to  the  arsenic  and  mercur\'. 

Arsenic  has  been  used  in  some  forms  of  trypanosoma  infection  in 
animals,  and  has  been  found  to  improve  similar  conditions  in  man. 
The  ordinary-  ]:)reparations  are  less  often  used  than  atoxyl  and  related 
substances,  })ut  the  trypanosomes  show  less  tendency  to  become  resis- 
tant to  the  inorganic  forms  and  it  is  now  reconunended  that  these 
diseases  should  })e  treated  by  both  inorganic  and  organic  compounds. 
Arsenic  is  undoubtedly  of  great  benefit  in  these  diseases,  relieving  the 
synii)t<)ms  and  i)rolonging  life  even  in  those  cases  in  which  it  does  not 
actually  cure  the  infection. 

Arsenic  is  in  the  great  majority-  of  cases  prescribed  in  the  form  of 
Fowler's  solution.  It  is  generally  advisable  to  commence  with  small 
doses,  and  to  increase  them  as  tolerance  is  de\eloped,  but  some 
authorities  advise  large  doses  from  the  outset.  Arsenic  is  always 
])r('S(ril)ed  to  be  taken  after  meals,  in  order  to  avoid  any  possible  action 
on  the  digestion.  Several  authors  have  reccmunended  tlie  hypodermic 
injections  of  Fowler's  solution  diluted  with  two  parts  of  water.  (Dose 
O.h  c.c.  (S  mills.)).  Arsenic  is  contraindicated  in  cases  of  irritation  of 
the  stomach  and  bowel,  and  is  gencrallN  avoided  during  acute  fever, 
e\ce])t  in  inalaria. 

If  s\iiii)tonis  of  chronic  ])oisoning  begin  to  assert  themselves,  the 
drug  ninst  be  discontinued  at  once.  The  first  symptoms  are  generally 
disordered  digestion,  loss  of  a|)petite  and  discomfort   in  the  stomach 


ARSENIC  001 

region,  a  feeling  of  constriction  in  the  throat,  and  rechiess  and  swelling 
of  the  conjunctiva  and  eyelids. 

In  Acute  Arsenic  Poisoning  the  stomach  ought  to  be  emptied  at  once 
hy  means  of  the  stomach  tube  or  by  an  emetic  (apomorphine).  The 
stomach  washing  is  to  be  continued  for  some  time,  as  arsenic  is  very 
insoluble.  Iron  or  magnesium  preparations  have  been  advised  in 
order  to  form  a  loose  chemical  combination  with  the  arsenic;  freshly 
precipitated  iron  hydrate  formed  by  adding  magnesia  to  a  solution 
of  iron  sulphate  forms  the  well-known  arsenic  antidote,  or  magnesia 
alone  is  sometimes  given  shaken  up  with  water.  Experiments  on 
animals  show  that  these  antidotes  are  useless  and  that  reliance  is  to  be 
placed  on  repeated  and  copious  lavage  only. 

The  collapse  is  treated  by  the  ordinary  measures,  warmth  and 
stimulants,  such  as  caffeine  and  digitalis.  In  chronic  poisoning, -the 
paralysis  is  treated  by  stimulating  the  muscles  with  the  galvanic  cur- 
rent, the  other  symptoms  by  suitable  general  treatment. 

Bibliography. 

A  very  complete  account  of  the  action  of  arsenic  is  given  by  Wertheimer  in  RicheCs 
Dictionnaire  de  Physiologie,  i,  p.  674.  Among  the  numberless  papers  on  Arsenic  the 
following  may  be  mentioned: 

Boehm  u.  Unterberger.     Arch.  f.  exp.  Path.  u.  Pharm.,  ii,  p.  89. 

Kossel.     Ibid.,  v,  p.  128. 

Gies.     Ibid.,  viii,  p.  175. 

Saikowsky.     Virchow's  Arch.,  xxiv,  p.  73. 

Schulzu.  Binz.  Arch.  f.  exp.  Path.  u.  Pharm.,  xi,  pp.  131,  200;  xiii,  p.  256;  xiv,  p. 
345;    XV,  p.  322;    xxxvi,  p.  275;    xxxviii,  p.  259;    xli,  p.  179. 

Husemann.     Deutsch.  med.  Woch.,  1892,  p.  1081. 

Lesser.     Virchow's  Arch.,  Ixxiii  and  Ixxiv. 

Heffter.  Arch.  f.  exp.  Path.  u.  Pharm.,  xxxi,  p.  257;  Arch,  internat.  de  Pharmacodyn- 
amique,  xv,  p.  399. 

Engel.     Virchow's  Arch.,  cxxxv,  p.  369. 

Brouardel  et  Pouchet.     Bull,  de  I'acad.  de  med.,  1889,  p.  915. 

Dana.     Brain,  ix,  p.  456. 

DaCosta.     Phila.  Med.  Times,  1881,  p.  385. 

Krehl.     Deutsch.  Arch.  f.  kHn.  Med.,  xliv,  p.  325. 

Kreyssig.     Virchow's  Arch.,   cii,  p.  286. 

Huber.     Ztschr.  f.  klin.  Med.,  xiv,  p.  444. 

Erlicki  u.  Rybalkin.     Arch.  f.  Psychiatrie,  xxiii,  p.  861. 

Ringer  and  Murrell.     Journ.  of  Physiol.,  i,  p.  213. 

Nunn.     Ibid.,  i,  p.  247. 

Putnam.     Boston  Medical  and  Surgical  Journ.,  cxx,  p.  235. 

Bettmann.     Ziegler's  Beitrage,  xxiii,  p.  377. 

Loew.     Pfliiger's  Arch.,  xl,  p.  444. 

Stockman  and  Greig.     Journ.  of  Physiol.,  xxiii,  p.  376;  Journ.  of  Path.,  1903. 

Reynolds  and  others.     Lancet  and  British  Med.  Journal,  1900,  ii,  and  1901,  i  and  ii. 

Morishima.     Arch,  internat.  de  Pharmacodyn.,  vii,  p.  05. 

Heffter.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlvi,  p.  230.     (Cacodylates.) 

Report  of  the  Royal  Commission  on  Arsenical  poisoning,  1903. 

Cloetta.     Arch.  f.  exp.  Path.  u.  Pharm.,  liv,  p.  196. 

Hausmann.     Pfliiger's  Arch.,  cxiii,  p.  327. 

Igersheimer  and  Rothnian.     Ztschr.  f.  phys.  Chem.,  lix,  p.  256. 

Saneyoshi.     Zeitschr.  f.  exp.  Path.,  xiii,  p.  40. 

Gunn  and  Feltham.     Brit.  Med.  Journ.,  Jan.  21,  1911. 

Laqueur  and  Ettinger.     Zeitschr.  f.  phys.  Chem.,  Ixxix,  p.  1. 

Neuhaus.     Arch,  internat.  de  Pharmacodyn.,  xx,  p.  393. 

Stadelmann.     Arch.  f.  exp.   Path.  u.  Pharm.,  xvi,  p.  221. 

Minkowski  u.  Naunyn.     Ibid.,  xxi,  p.  14. 

Meissner.     Zeitschr.  f.  exp.  Path.,  xiii.,  p.  284. 


G02  SUBSTANCES  ACTING  AFTER  ABSORPTION 


LVI.    ORGANIC  ARSENIC  COMBINATIONS. 

Inorganic  arsenic  has  long  had  some  reputation  in  the  treatment  of 
mahiria  and  syi)hilis;  in  the  latter  it  has  been  used  along  with  mercury 
in  the  well-known  DonoN'an's  solution.  These  diseases  have  been  shown 
to  arise  from  animal  ])arasites  living  in  the  blood  and  tissues,  and  when 
the  sleeping  sickness  of  Africa  was  found  to  arise  from  trypanosomes, 
another  protozoan  parasite,  inorganic  arsenic  was  used  to  treat  it. 
The  results  were  disappointing,  as  the  quantity  of  arsenic  that  could  be 
given  was  limited  owing  to  its  poisonous  action  on  the  patient.  For 
inorganic  arsenic  proved  to  have  little  specific  affinity  for  the  parasite; 
in  Ehrlich's  j)hraseology,  it  was  not  parasitotropic,  while  it  was  very 
])oison()ns  to  the  tissues  of  the  host,  or  strongly  organotropic.  In  the 
test-tube  the  inorganic  arsenic  preparations  are  very  ])()isonous  to 
the  try])anosonies,  and  they  would  doubtless  be  equally  destructive 
in  the  tissues  if  they  could  be  applied  there  without  the  destruction 
of  the  host. 

Some  organic  preparations  of  arsenic  proved  available  for  treatment, 
the  first  being  Atoxyl,  or  sodium  arsaiiilate.  Later  a  modification  of  atoxy  1 

r'      A   rwOH  /As=As\ 

HC  /\  CH  HC  /\  CH 


HC  r     ^  CH 


HC  s^^  CH  NH2— C  I      J  CH  HC  I       J  NH2 

C— NH2  C— OH  C— OH 

Atoxyl.  Salvarsan. 

C— As=As— C    . 


HC 


NH.— C 


\/ 


CH  HC 


CH  HC 


CH 


\y  '^^'^CH^OSONa 


C— OH  C— OH 

Neosalvarsan. 

OH 

known    as    Arsaceiin    (acetylatoxyl,    CH3CONH — C6H4 — ^AsO<^^t 

was  found  more  active  in  combating  trypanosoma  infections.  These 
combinations  ])rovcd  useful  in  syi)hilis  also,  hut  while  destroying  the 
parasites  in  these  diseases,  they  were  not  dcNoid  of  deleterious  action  in 
man  and  \va\v  already  almost  disappeared  from  therapeutics.  Ehrlich 
soon  ])ointed  out  that  atoxyl  has  practically  no  action  on  trypanosomes 
in  test-tube  experiments  and  only  gains  its  ])arasiticide  action  in  the 
tissues.  He  ex])lains  this  by  the  view  that  the  penta\aleiit  arsenic 
comi)ounds,  such  as  atoxyl  and  arsenic  acid,  are  really  inactive  in 
themscKes  and  only  acfinire  activity  when  they  are  changed  to  the 
tri\alent  arsenic,  such  ;is  exists  in  arsenites. 

Tills  led  him  to  seek  tor  organic  compounds  in  which  the  arsenic  is 
trixalent,  and  two  of  these  were  introduced  i)y  him,  Ansoiopluni/lyli/cui 


ORGANIC  ARSENIC  COMBINATIONS  003 

and  Salvarsan  (AsC6H30HNH2)22H('l,  of  which  tlie  latter  has  been  very 
widely  used  in  the  treatment  of  syiihilis.  More  recently  a  modification 
of  saivarsan,  Neosalvarsan,  has  been  used  instead  of  the  parent  sub- 
stance. All  of  these  organic  compounds  are  much  less  poisonous 
to  man  and  the  higher  animals  than  inorganic  arsenic,  while  they 
maintain  the  poisonous  action  toward  the  protozoa  that  infect  the 
blood  and  tissues.  In  other  words  they  are  less  organotropic  and  more 
parasitotropic.  Ehrlich  supposes  that  certain  parts  of  the  molecule 
in  these  compounds  attach  themselves  to  the  parasites,  and  that  these 
ha]it()phoric  groups  then  allow  the  poisonous  part,  or  toxophoric  groups, 
to  act  on  the  protozoa.  The  tissues  of  the  mammals  do  not  afi'ord 
points  of  attachment  for  the  haptophoric  groups  and  therefore  are 
not  attacked  by  the  toxophoric  radical.  A  simpler  view  is  that  the 
organic  compounds  permeate  readily  into  the  parasite  and  there  are 
decomposed,  possibly  to  inorganic  arsenic,  and  thus  prove  poisonous 
to  the  protozoa;  the  mammalian  cell  is  less  readily  permeated  by  the 
organic  fornis  and  thus  escapes  being  destroyed  by  them. 

The  treatment  of  trypanosoma  infections  wdth  arsenic  preparations 
has  i)roved  less  successful  than  the  first  applications  seemed  to  promise, 
owing  to  the  parasites  rai)idly  becoming  tolerant  to  the  drug.  If  an 
animal  infected  with  trypanosomes  receives  an  injection  of  atoxyl,  the 
parasites  disappear  from  the  blood  and  none  may  be  found  in  it  for 
many  days  or  weeks;  then  a  few  reappear  and  rapidly  multiply  but 
are  again  destroyed  by  a  second  dose;  the  interval  before  they  are 
again  seen  in  the  blood  is  shorter,  and  becomes  shorter  with  each  suc- 
ceeding hijection  until  atoxyl  no  longer  frees  the  blood  from  trypano- 
somes even  in  the  maximal  dose  which  can  be  given  without  injury 
to  the  host.  If  a  second  animal  is  now  infected  with  the  blood  of  the 
first  containing  these  resistant  trypanosomes,  it  is  not  improved  by 
atoxyl,  the  descendants  of  the  resistant  type  maintaining  their  tolerance 
of  atoxyl  through  an  indefinite  series  of  generations.  This  form  of 
resistance  appears  to  arise  from  a  process  of  selection  by  the  survival 
of  the  most  tolerant.  The  first  dose  of  atoxyl  destroys  all  but  the  most 
resistant  of  the  trypanosomes,  and  these  multiply  and  again  the  most 
resistant  survive  the  second  dose,  and  thus  a  strain  is  eventually  reached 
which  is  as  resistant  to  the  atoxyl  as  the  tissues  of  the  host.  This 
change  in  the  character  of  the  trypanosomes  depends  on  their  asexual 
generation  and  is  readily  intelligible  when  it  is  realized  that  successive 
generations  are  really  only  fragments  of  the  original  resistant  individuals. 
Whenever  a  sexual  cycle  is  interposed,  all  the  resistance  to  atoxyl  is 
lost;  and  except  from  experimental  inoculation  the  transmission  of 
the  trypanosoma  diseases  from  one  host  directly  to  another  must  be  a 
rare  occurrence.  A  strain  of  trypanosomata  which  has  developed 
tolerance  for  one  of  the  organic  arsenical  preparations  (arsenic-fast) 
is  generally  tolerant  of  the  others  also,  but  not  in  such  high  degree 
of  inorganic  arsenic. 

The  same  tolerance  may   be  developed  in  trypanosomata  treated 
with  other  remedies;  for  example,  some  of  the  dyes  are  poisonous  to 


not  SUBSTANCES  ACTING  AFTER  ABSORPTION 

certain  s])ocics,  but  the  same  resistance  is  developed  towards  these.  A 
strain  which  is  arsenic-fast  is  as  siisce])til)lc  to  these  dyes  as  an  untreated 
strain,  and  simihirly  a  strain  which  is  resistant  to  a  dye  (r.  r/.,  tryi)an- 
rcd)  shows  no  resistance  to  arsenic. 

i .  Cacodylates. 

The  carHcst  of  the  organic  arsenic  compounds  to  be  used  in  medicine  was 
s()(Hum  cacodylate,  (CH,,).2AsO.ONa,  which  is  relatively  fccljle  in  action  as  it 
releases  only  small  (luantilies  of  arsenic  ion  in  the  tissues.  Most  of  the  caco- 
dylate is  eliminated  unchanged  in  the  urine,  some  appears  to  be  reduced  to 
cacodvl,  (CH3)4As>,  which  is  excreted  in  the  breath  and  lends  it  an  odor  like 
garlicj  while  another  smaU  proportion  is  changed  to  the  inorganic  form  and 
exercises  the  typical  arsenic  action.  The  amount  which  un(lergoes  this  trans- 
mutation is  unknown  and  probably  varies  in  different  individuals  and  in  dif- 
ferent circumstances.  Sodium  cacodylate  has  been  advised  in  syphilis.  It  is  a 
white  crvstalline  salt  readilv  soluble  in  water.  Dose,  ^-1  gr.  Another  nearly 
related  salt  has  been  introd'uced  as  Arrhotal  (CH3AsO(ONa)2),  and  resembles 
cacodylate  in  action. 

2.  Atoxyl. 

Atoxyl,  or  sodium  arsanilate  (NH2C6H40AsOH.OXa)  has  recently  been  used 
extensively  in  trypanosome  infections,  in  which  it  seems  to  present  some 
advantages  over  the  inorganic  arsenic  salts.  It  is  absorbed  rapidly  and  cir- 
culates in  the  blood  longer  than  the  arsenites,  which  are  taken  up  by  the  tissues 
rapidly  and  thus  can  exert  only  a  transient  action  on  parasites  li\'ing  in  the 
plasma.  Atoxyl  is  excreted  in  the  urine  for  the  most  part  unchanged,  but  a 
small  proportion  undergoes  decomposition  and  is  believed  to  liberate  the 
arsenious  ions.  Trypanosomes  are  not  affected  by  atoxyl  outside  the  body 
more  than  by  many  other  substances,  and  there  has  been  some  discussion  as  to 
how  its  specific  action  arises  in  the  body.  P^hrlich  holds  that  it  is  partially 
reduced  in  the  tissues  and  that  the  product  of  reduction  is  the  active  tryi)ano- 
cide,  and  he  has  shown  that  such  reduced  Ijodies  act  very  powerfully  on  try- 
panosomes in  test-tube  experiments;  on  the  other  hand,  it  has  not  been  proved 
that  this  reduction  occurs  in  the  tissues.  Others  believe  that  the  inorganic 
arsenic  formed  from  atoxyl  is  the  active  agent,  and  there  is  no  question  that 
inorganic  arsenic  destroys  the  parasites  both  in  the  blood  and  in  the  test-tube; 
the  more  powei-ful  action  of  the  small  (luantitics  of  arsenic  liberated  from 
atoxyl  in  the  body  may  perhaps  l)e  explained  by  its  being  freed  in  the  l)lood()r 
in  the  interior  of  the  parasite  into  which  the  atoxyl  has  ixnietrated,  while  in- 
organic arsenic  leaves  the  blood  very  rapidly.  Strong  evidence  in  favor  of  the 
view  that  atoxyl  acts  in  virtue  of  its  liberating  arsenic  is  offered  by  the  observa- 
tion that  trypanosomes  which  have  become  resistant  to  atoxyl  have  also  a  low 
susceptibility  to  arsenic. 

In  a  nunihcr  of  cases  atoxyl  has  given  rise  to  poisoning  m  man,  the  symii- 
toms  being  dryness  of  the  throat,  headache,  giddiness,  fever,  colic,  vomiting 
and  diarrluca,  nephritis,  and  paresis  of  the  lower  limbs;  the  most  senou.>> 
effects,  however,  arc  disturbances  of  vision,  which  may  advance  to  total  and 
permanent  blindness.  In  animals,  ataxia  and  tremors  arc  seen,  especially 
in  the  cat,  and  renal  ha-morrhagcs  in  the  dog.  Blindness  has  also  been 
induced  experimentally  in  animals,  and  is  found  to  arise  from  degeneration  of 
the  ganglion  cells  of  the  retina  and  lal-r  of  the  fibres  of  the  optic  nerve.  Tlicsc 
symptoms  arc  not  those  ordinarily  induced  by  arsenic  in  chronic  poisoning, 
and  it  has  been  suggested  that  the  aniline  component  is  responsible  for  them, 
but  this  does  not  seem  jn-obable;  and  they  often  .supervene  after  atoxyl  has  been 
discontinued,  so  that  it  seems  improbable  that  this  substance,  which  is  so  rapidly 


ORGANIC  ARISEN  Id  COMBINATIONS  005 

eliminated,  is  itself  the  aseut.  It  seems  likely  that  these  symptoms  are  again 
the  result  of  the  arsenic  liberated  from  the  atoxyl,  and  that  the}''  are  different 
from  those  oi'dinarily  seen  imder  arsenic,  because  the  arsenic  is  liberated  in 
unusual  i^arts  of  the  body,  owing  to  the  atoxyl  penetrating  where  the  inorganic 
forms  fail  to  reach. 

Atoxyl,  sodium  arsanilate  (CeHrNAsOsNa),  is  a  white  crystalline  i)owder 
containing  27.2  per  cent,  of  arsenic  metal,  soluble  in  six  parts  of  water  or  about 
125  parts  of  alcohol.  It  has  a  faint  saline  taste.  Dose  hypodermically,  0.1-0.3 
G.  (l|-5  grs.)  per  day  in  10  per  cent,  solution. 

A  number  of  other  arsenic  compounds  similar  to  atoxyl  have  been  tested 
recently  in  trypanosomiasis  and  other  diseases.  Of  these  Soamine  is  practically 
identical  with  atoxyl,  differing  only  in  the  amount  of  water  of  crystallization. 
Arsacetin  is  acetyl-atoxyl  and  resembles  the  parent  substance  closely  in  effects. 

Atoxyl  and  its  allies  were  introduced  for  the  treatment  of  trypanosomiasis, 
in  particular  in  sleeping  sickness.  And  it  still  continues  to  hold  a  position  for 
this  purpose,  for  it  is  not  yet  established  that  the  newer  preparations  are  superior 
to  it  in  trypanosomicidal  power.  But  the  hopes  which  were  at  first  entertained 
that  it  would  prove  a  cure  for  the  disease  are  now  dissipated;  atoxyl  appears 
to  act  efficiently  on  the  parasites  in  the  blood,  but  has  less  effect  on  those  which 
have  infected  the  lymph  glands,  and  apparently  does  not  reach  those  in  the 
central  nervous  sj^stem  in  efficient  concentrations.  It  clears  the  blood  of  the 
parasites,  but  the  supply  is  constantly  renewed  from  the  foci  in  the  nervous 
axis  and  eventually  the  parasites  become  resistant.  In  sleeping  sickness  atoxyl 
may  alleviate  the  symptoms  and  prolong  life  but  a  cure  of  the  disease  from  its 
use  is  very  rare.  It  was  also  proposed  to  use  it  in  syphilis,  but  fortunately 
before  it  attained  popularity,  the  frecjuency  with  which  it  causes  blindness 
and  other  toxic  effects  was  recognized  and  since  then  this  group  of  compounds 
has  been  regarded  as  too  dangerous  to  use. 

3.    Salvarsan. 

Salvarsan,  or  arsenobeiizol  (p-dih\droxy-m-diamino-arsenobenzene) , 
was  introduced  by  Ehrlicli  for  the  treatment  of  syphilis  and  has 
enjoyed  great  popularity  in  the  last  few  years.  It  differs  from  the 
organic  arsenic  compounds  so  far  discussed  in  the  fact  that  it  contains 
arsenic  in  the  triad  form,  and  thus  corresponds  to  the  arsenites,  while 
in  atoxyl  the  arsenic  is  pentad  and  corresponds  to  the  arsenates.  Atoxyl 
itself  appears  to  act  only  when  it  is  reduced  to  triad  arsenic  in  the  body. 

Ehrlich  introduced  arsenophenylglycin  about  the  same  time  as 
salvarsan,  but  the  latter  proved  so  much  superior  that  the  former  has 
not  been  much  used. 

Salvarsan  was  at  first  injected  into  the  muscles  in  man,  but  it  tended 
to  be  deposited  locally  and  to  give  rise  to  pain,  swelling  and  infiltration, 
and  was  absorbed  only  slowly.  The  intravenous  administration  was 
therefore  adopted  and  has  become  the  ordinary  method,  although 
some  authorities  hold  that  the  intramuscular  administration  was 
abandoned  prematurely. 

When  salvarsan  is  injected  intravenously,  there  are  as  a  general 
rule  no  symptoms  elicited,  but  in  individual  cases  effects  varying  from 
com])aratively  tri\'ial  disturbance  to  grave  and  even  fatal  issues  have 
been  met  with. 

The  symptoms  more  commonly  described  are  headache,  giddiness, 
nausea  and  malaise,  and  fever;  sometimes  vomiting  and  diarrhoea  occur, 


006  SUBSTANCES  ACTING  AFTER  ABSORPTION 

and  jaundice,  dyspna^a,  restlessness  and  tremors,  profuse  sweatinji, 
and  exanthemata  of  various  kinds  have  occasionally  been  seen.  In 
uraver  cases  crdema  and  c-yanosis  of  the  face,  with  cerebral  confusion 
ha\e  led  to  collapse,  coma,  and  death.  In  other  instances  con\ulsions 
have  occurred  several  days  after  the  injection,  aufl  high  fe^•e^  and  eoma 
ha\e  followed  from  encephalitis  and  meningitis;  it  is  not  yet  clear 
whether  nephritis  is  always  present  in  these  fatal  cases,  but  in  some 
at  least  it  has  been  shown  both  before  and  after  death.  Saharsan 
does  not  seem  to  act  on  the  o])tic  tract  as  atoxyl  does,  l)ut  in  a  number 
of  cases,  some  symptoms  have  arisen  from  disturbance  of  the  auditory 
nerve  or  from  paralysis  of  the  facial  or  of  other  nerves. 

The  cause  of  these  symptoms  has  been  much  discussed,  some  ascrib- 
ing them  not  to  the  direct  action  of  the  salvarsan  but  to  the  technique 
employed  or  to  the  flooding  of  the  tissues  with  the  proteins  of  the  i)ara- 
sites  destroyed.  Some  of  the  symptoms  have  been  attributed  to  acute 
arsenic  poisoning  and  present  some  analogies  to  that  condition;  thus  the 
exanthemata,  ^•omiting  and  diarrhoea  and  the  affections  of  the  nerves 
are  common  to  both.  But  exanthemata,  \omiting  and  diarrhcea  are  so 
often  observed  as  idiosyncrasies  in  the  use  of  other  drugs,  that  too  much 
imi^ortance  should  not  be  attached  to  this  analogy. 

Not  infrecpiently  swelling  and  oedema  occur  around  the  local  mani- 
festations of  syi)hilis  after  salvarsan  has  been  injected;  for  example 
when  salvarsan  is  administered  in  syphilitic  skin  eru])tions,  the  skin 
lesions  swell  up,  and  the  secretion  from  ulcers  is  increased  (Ilerxheimer). 
""J'his  may  perhaps  arise  from  the  poisonous  action  of  the  proteins  freed 
from  the  dead  spirochsetes. 

In  animals,  the  intravenous  injection  of  salvarsan  in  large  quantities 
causes  a  marked  fall  in  blood-pressure,  which  is  stated  to  resemble  that 
seen  under  arsenic  in  arising  in  part  from  direct  action  on  the  walls 
of  the  arterioles  and  capillaries,  in  part  from  central  action;  but  other 
observers  regard  it  as  due  to  salvarsan  weakening  the  heart.  In  man 
a  fall  of  blood-pressure  sometimes  follows  the  intra^•enous  injection, 
but  in  other  cases  no  change  in  the  circulation  is  seen  except  a  slight 
acceleration  of  the  heart. 

It  is  stated  that  in  animals  fatal  encephalitis  may  be  elicited  by 
salvarsan,  with  hannorrhages  and  thrombosis  of  the  \essels;  the 
encephalitis  met  with  in  a  few  cases  in  man  would  thus  appear  to  arise 
from  the  direct  action  of  the  drug. 

And  in  rabbits  large  doses  are  found  to  induce  nei)hritis,  which,  like 
that  induced  by  inorganic  arsenic,  afl'ects  the  vessels  rather  than  the 
tubules  of  the  "kidney;  animals  in  which  this  vascular  nei)hritis  has 
pre\'iously  been  induced  by  cantharides  prove  very  susceptible  to 
salvarsan.  It  has  also  been  shown  (Alwens)  that  when  the  tricuspid 
valves  of  th(>  heart  have  been  IujuhmI  in  animals,  they  can  be  ])oisoned 
by  smaller  (piantities  of  salvarsan  than  usual, and  this  has  been  attributed 
to  the  drug  acting  more  strongly  on  the  congested  abdominal  ()rgans, 
('specially  the  liver.  Neosalvarsan  has  much  less  tendency  to  induce 
nephritis  than  salvarsan. 


ORG  A  XI( '  A  RSKMC  ( 'OMBINA  TIONS  607 

Saharsau  appears  to  ha\e  the  same  effect  in  accelerating  the  forma- 
tion of  red-blood  cells  as  is  possessed  by  the  inorganic  arsenic  prepara- 
tions. 

Saharsan  is  fonnd  to  destroy  cnltures  of  s])iroch;ctc  in  the  test-tube 
only  in  a  concentration  of  about  one  in  1000,  but  its  activity  is  greatly 
enhanced  when  it  is  digested  with  tissues;  these  presumably  form 
inorganic  arsenic  compounds  which  are  30-40  times  as  toxic  to  the 
parasites. 

Excretion. — The  intramuscular  or  subcutaneous  injection  of  saharsan 
is  followed  by  the  appearance  of  arsenic  in  the  urine  and  in  smaller 
quantities  in  the  stools;  it  generally  disappears  from  the  urine  in  10-14 
days  while  it  may  be  found  in  the  stools  longer,  but  the  duration  depends 
on  the  extent  to  which  it  forms  a  local  deposit  in  the  muscles;  it  does 
not  appear  that  any  saharsan  is  excreted  unchanged  in  the  urine  after 
the  intramuscular  injection.  When  it  is  injected  intravenously,  sal- 
\arsan  appears  unchanged  in  the  urine  in  5-10  minutes  and  persists 
in  this  form  for  5-0  hours;  thereafter  arsenic  is  found  in  the  urine  for 
about  three  days,  but  it  is  imknown  in  what  combination  it  exists. 
It  is  excreted  in  the  stools  in  smaller  proportions  than  in  the  urine,  but 
for  a  longer  time.  It  disappears  from  the  blood  at  about  the  same  time 
as  from  the  excretions,  but  may  be  foimd  in  the  li\  er,  bone-marrow 
and  kidney  rather  later;  an  arsenic  reaction  may  be  obtained  from 
the  li\er  and  marrow  as  late  as  ten  days  after  the  intra^■enous  injection 
in  animals,  but  no  arsenic  is  to  be  found  in  any  of  the  organs  after  15 
days. 

It  would  thus  appear  that  after  its  intra^•enous  injection  salvarsan 
is  excreted  in  considerable  quantity  unchanged,  but  after  some  hours 
an  miknown  arsenic  compound  takes  its  place  and  persists  for  several 
days.  Arsenic  corresponding  to  50-75  per  cent,  of  that  injected  has 
been  regained  from  the  urine;  the  fate  of  the  remaining  25  per  cent, 
is  unknown.  Some  appears  to  be  stored  in  the  liver  and  lione  marroAv 
temporarily.  Arsenic  is  not  found  in  the  cerebrospinal  fluid  after  the 
intravenous  injection  of  salvarsan. 

After  the  injection  of,  neosalvarsan,  formaldehyde  appears  in  the 
urine  from  the  decomposition  of  the  molecule,  but  this  disappears  in 
a  few  hours;  the  excretion  of  neosalvarsan  otherwise  resembles  that  of 
salvarsan. 

Salvarsan,  diamino-dihvdroxvl-arsenobenzene  livdrochloride,  HCINH2- 
OHC6H3As  =  ASC6H3OHNH2HCI+2H2O,  is  a  yellow,  crystalline  powder  contain- 
ing 31.5  per  cent,  of  arsenic  metal  and  reiidily  oxidizing  in  the  air;  it  is  accord- 
ingly kept  in  vacuum  tubes.  It  is  readih'  soluble  in  water  with  an  acid  reaction. 
Dose,  0.3-0.6  G.  (5-9  grs.)  bj'  intravenous  or  intramuscular  injection.  The 
salvarsan  tube  should  not  be  opened  until  required.  The  contents  are  dissolved 
in  sterilized  saline  (0.9  per  cent.)  and  neutralized  to  litmus  with  normal  caustic 
soda  solution  (0.1  c.c.  of  normal  XaHU  is  required  for  each  0.1  G.  of  salvarsan); 
a  precipitate  is  formed  which  redissolves  on  shaking.  The  solution  should  be 
\evy  dilute  for  intravenous  injection,  at  least  300  c.c.  being  used  for  0.6  G. 
salvarsan  and  more  commonlj'  500  c.c.  or  more.  Great  care  must  be  taken  that 
the  solution  is  not  injected  into  the  tissues  around  the  vein  as  it  causes  intense 
pain  and  induration. 


608  srnsrANCEs  acting  after  absorption 

Salvarsaii  is  seldom  injected  into  the  nius!-les  now  as  it  causes  intense  pain  and 
is  often  deposited  locally;  when  this  method  is  used  a  strong  solution  (6-10  c.c.) 
is  neutralized  and  is  not  diluted  as  for  intravenous  use. 

Neosalvausan,  NHo()HC6lI.,As  =  AsCcH30HNHCH.,OSONa,  is  a  yellow 
crystalline  powder  rcadil.y  oxidizing  when  exposed  to  the  air  and  soluble  in 
water  with  a  neutral  reaction;  along  with  the  arsenical  compound  it  contains 
some  inorganic  sodium  salts  so  that  three  parts  of  neosalvarsan  are  eciuivalent 
to  two  parts  of  salvarsan.  Dose,  0.3-0.9  G.  (5-15  grs.)  by  intravenous  or  intra- 
muscular injection.  The  contents  of  a  newly  opened  tul:)e  are  dissolved  in 
25  c.c.  freshly  distilled  water  for  each  0.15  G.  neosalvarsan,  and  injected;  the 
solution  is  neutral  in  reaction  and  thus  requires  jio  addition  of  alkaU  as  in  the 
case  of  salvarsan. 

Salvarsan  and  neosalvarsan  tend  to  oxidize  very  rapidly  in  the  air  with  the 
formation  of  the  i)oisonous  paramidophenolarsenic  oxide.  They  must  be  used 
immediately  after  solution  and  the  solution  should  be  made  with  freshly  dis- 
tilled water. 

Therapeutic  Uses. — Salvarsan  was  introduced  by  Ehrlich  for  the 
treatment  of  syjihilis  and  has  been  succeeded  by  neosalvarsan,  which 
lias  the  ad\antage  of  being  available  with  less  manipulation  and  thus 
pronn'ses  to  rei)lace  the  mother  substance.  At  first  it  was  hoped  that  a 
single  injection  of  saharsan  would  suffice  to  destroy  tlie  sj)irochifte 
of  syphilis  and  realize  the  ideal  of  complete  sterilization  of  the  tissues 
as  far  as  the  virus  of  this  disease  was  concerned.  And  although  this 
hope  has  not  been  entirely  fulfilled,  the  introduction  of  these  arsenical 
compounds  in  the  treatment  of  syphilis  is  a  very  im])ortant  advance 
in  medicine.  Very  frequently  a  single  injection  of  saharsan  frees  the 
blood  from  parasites  within  a  few  hours,  and  the  Wassermann  reaction, 
wliich  is  specific  for  syphilis,  disappears;  in  a  certain  numl)er  of  cases 
the  disease  is  healed,  but  in  others  the  reaction  returns.  Some  weeks 
or  months  later  the  sjiirochjetes  can  be  found  again  and  sym])toms 
of  secondary  syphilis  begin  to  appear.  The  first  injection  suffices  to 
destroy  the  great  mass  of  parasites,  but  a  few  siu-vive  and  reinfect  the 
tissues.  The  same  tolerance  develops  as  has  already  been  discussed 
under  the  atoxyl  treatment  of  trypanoscmiiasis,  in  which  it  was  first 
observed. 

It  is  now  advised  therefore  that  salvarsan  or  neosalvarsan  should  be 
injected  repeatedly  at  interxals  of  one  or  two  weeks,  and  that  vigorous 
mercurial  treatment  should  be  initiated  inunediately  after  the  first 
saharsan  injection  and  carried  out  as  was  customary  before  these  new 
arsenicals  were  introduced.  The  treatment  with  arsenic  compounds 
and  mercury  should  be  instituted  as  soon  as  the  diagnosis  is  made,  as  the 
action  of  these  sjiecifics  is  much  more  efficient  when  the  invasion  of  the 
j)arasitcs  is  only  beginning  and  before  they  have  reached  inaccessible 
positions  in  the  tissues.  In  the  later  stages,  salvarsan  is  also  \ery  valu- 
able, but  when  the  parasites  are  distributed  in  the  central  nervous 
system  it  appears  to  be  imable  to  reach  them,  and  while  those  in  the 
blood  and  organs  may  be  destroyed,  the  symi)toms  of  nervous  sclerosis 
often  show  little  imj^rovement;  c\-cn  in  these  ner\ous  {|)arasy])hilitic) 
all'cctions  the  process  seems  to  be  arrested  or  retarded  in  some  cases, 
liowe\er. 


ORGANIC  ARSENIC  COMBINATIONS  009 

Sal\iirs;m  ditViTs  from  ineniiry  in  syi)]iilis  in  its  firciitcr  rai)i(lity; 
the  i)arasites  disappear  after  mercury  treatment  just  as  after  salvarsau, 
but  a  steriliziufi;  eoueentration  of  mercury  cau  be  reacJied  only  after 
several  days,  and  frequently  entails  more  or  less  ])ronounced  symi)toms 
of  mercurialism.  The  intravenous  injection  of  salvarsan  on  the  other 
hand  acts  within  a  few  hours,  but  most  of  the  drug  is  excreted  within 
three  days,  and  the  survi\ing  ])arasites  multiply'  unrestrained.  When 
salvarsan  and  mercury  are  used  together,  the  immediate  action  of  the 
one  is  obtained  and  is  reinforced  by  the  slower  and  prolonged  action 
of  the  other.  In  addition,  it  seems  likely  that  some  parasites  escape 
owing  to  their  being  only  slightly  susceptible  to  salvarsan  (see  p.  603), 
but  the  chances  are  small  that  the  same  individuals  have  a  low  susce])ti- 
bility  to  salvarsan  and  also  to  mercury.  The  combined  treatment  with 
arsenic  and  mercury  may  thus  be  justified  by  theoretical  considerations, 
and  has  been  abundantly  supported  l)y  clinical  experience  in  the  last 
few  years. 

Salvarsan  is  now  used  almost  exclusively  by  intravenous  injection,  but 
there  is  some  tendency  to  recur  to  the  intramuscular  use  in  the  case 
of  neosalvarsan,  though  it  is  unlikely'  that  this  will  prove  as  efficient. 

In  the  treatment  of  several  other  protozoal  diseases,  salvarsan  has 
l)roved  as  successful  as  in  that  of  syphilis.  Thus  in  framboesia  (yaws), 
recurrent  fever,  and  Vincent's  angina,  it  is  remarkably  efficient,  and  in 
spirillosis  of  the  lower  animals  an  equal  success  has  followed  its  use. 
In  malaria  salvarsan  is  inferior  to  quinine,  and  in  sleeping  sickness  it 
appears  to  be  less  useful  than  atoxyl.  Neosalvarsan  has  been  applied 
locally  in  2  per  cent,  solution  in  syphilitic  keratitis  and  in  spirillar 
diseases  of  the  mouth  and  teeth,  w4th  good  results. 

In  a  number  of  diseases  in  which  inorganic  arsenic  has  previously 
been  used,  salvarsan  has  been  given  as  a  substitute;  thus  pernicious 
anaemia,  rheumatism  and  various  skin  diseases  have  been  treated  with 
it,  but  the  results  do  not  seem  better  than  those  obtained  from  the  older 
arsenical  preparations. 

In  cases  of  emaciation  and  malnutrition,  the  organic  arsenic  prepa- 
rations are  to  l>e  used  with  special  care  and  in  low  doses,  and  in  disease 
of  the  heart,  ^■essels,  or  brain,  and  in  \evy  old  and  feeble  persons  or  those 
suffering  from  nephritis  or  diabetes,  saharsan  should  not  be  employed 
except  under  special  precautions.  In  such  cases  the  patient  should  be 
prepared  for  the  injection  as  if  for  an  oi)eration  and  should  not  be 
allowed  to  resume  his  ordinary  occupation  for  several  days;  and  the 
doses  should  ])e  reduced  in  amount. 

Bibliography. 

Ehrlich.     Sleeping  Sickness  Bulletin,  vols.  i-iv. 
Ehrlich.     Abhandlungen  iiber  Salvarsan,  vols,  i-iii. 

Mentberger.  Entwickelung  und  gegenwartiger  Stand  der  Arsentherapie  der  Syphilis, 
1913. 

Ahdin.     Arch.  f.  exp.  Path.  u.  Pharm.,  Ixxv,  p.  317. 
Bronfenhrenner  and  Noguchi.     Jour,  of  Pharmacology,  iv,  p.  333. 
39 


PART  in. 
THE  HEAVY  METALS. 


HEAVY  METALS. 

A  LARCiE  number  of  important  drugs  belonging  to  the  chemical 
series  of  heavy  metals  resemble  each  other  so  closely  in  their  action  in 
living  organisms  that  they  may  be  readily  grouped  together  in  a  divi- 
sion of  the  pharmacological  system.  Some  authors  include  in  this 
series  arsenic  and  antimony,  but  the  former  presents  so  many  analogies 
to  phosphorus  in  its  effects  that  it  is  preferable  to  treat  it  apart  from  the 
heavy  metals.  Antimony  is  certainly  as  closely  related  to  arsenic  as  to 
this  group,  and  may  be  regarded  as  a  connecting  link  between  them. 

The  metals  as  such  do  not  induce  any  symptoms  except  from  their 
mechanical  properties.  Thus  mercury  may  be  swallowed  in  large 
quantities  without  causing  mercurial  poisoning,  and  silver  or  copper 
coins  are  equally  devoid  of  effect  as  poisons.  They  are  active  only 
when  they  are  capable  of  dissociation  into  ions  of  the  metal  or  of  an 
oxide.  Thus  potassium  ferrocyanide  does  not  cause  any  symptoms 
of  iron  poisoning  when  it  is  injected  into  a  vein,  because  the  iron  passes 
through  the  body  undissociated,  and  any  effects  are  due  to  the  ferro- 
cyanide ion  and  not  to  the  iron.  In  the  same  way  compounds  of  the 
metals  with  ethyl  and  methyl,  such  as  lead  triethyl,  have  an  action 
quite  different  from  that  of  lead,  as  long  as  they  remain  undecomposed  in 
the  tissues,  but  eventually  induce  metallic  poisoning,  as  they  are  broken 
up  into  bodies  from  which  the  lead  or  lead  oxide  ion  can  be  dissociated. 

The  action  of  the  heaAy  metals  consists  of  two  parts,  the  local  effects 
induced  at  the  point  of  application,  and  the  general  effects  which 
follow  the  absorption  of  the  poison  into  the  blood  and  tissues.  Either 
of  these  may  be  produced  alone  by  suitable  preparations  and  modes  of 
administration,  and  they  are  to  be  regarded  as  entirely  independent 
of  each  other. 

The  Local  Action  of  the  heavy  metal  series  is  due  to  their  precipitating 
proteins  in  very  dilute  solutions;  the  nature  of  this  action  is  not  quite 
established,  but  it  is  considered  by  most  authorities  that  no  true  chemical 
compound  between  the  metal  and  the  protein  is  formed,  but  that  the 
precipitate  is  of  the  nature  of  an  adsorption  complex.  Proteins  are  also 
thrown  out  of  solution  by  salts  of  the  alkalies  and  alkaline  earths,  but 
only  when  these  are  present  in  much  higher  concentration  than  is 
necessary  in  the  case  of  the  heavy  metals;  and  the  precipitate  formed 
by  the  salts  of  the  alkalies  is  reversible,  that  is,  it  can  be  redissolved 

b\-  the  addition  of  water. 

(611) 


612  THE  HEAVY  METALS 

W\\v]\  a  salt  of  a  lK'a\  y  nirtal  is  added  to  a  solution  of  e^g  allniiiiiii, 
or  similar  protein,  a  ])reeii)itate  is  formed  consisting  of  proteins  and  a 
variable  amount  of  the  metal  or  its  oxide,  while  free  acid  remains  in 
solution.  The  ])recipitate  is  insoluble  in  water  but  is  dissolved  by 
neutral  salts,  including  those  of  the  heavy  metals,  so  that  the  addi- 
tion of  more  metallic  salt  may  redissolve  the  precipitate;  similarly  the 
addition  of  more  protein  solution  may  redissohe  the  precipitate  by 
increasing  the  supplj^  of  neutral  salts.  The  precipitate  contains  the 
metal  in  an  insoluble  form,  and  the  latter  may  })e  detected  by  the 
ordinary  reactions;  thus  the  i)rotein  i)recipitate  from  iron  salts  is 
blackened  by  ammonium  sulphide  in  the  same  way  as  ordinary  iron. 

On  subjecting  these  precipitates  to  certain  chemical  manipulations, 
however,  the  metal  seems  to  become  more  firmly  attached  to  the  protein, 
for  ammonium  sulphide  acts  on  it  much  more  slowly.  The  metal  is 
then  said  to  be  masked,  because  its  presence  is  not  so  readily  detected 
as  in  ordinary  combinations.  Partially  masked  preparations  have  been 
formed  artificially,  but  in  the  body  the  process  is  carried  much  further, 
for  in  many  of  their  protein  compounds  the  metals  cannot  be  detected 
by  any  of  the  ordinary  tests,  however  long  the  reagents  may  remain  in 
contact  with  them,  and  their  presence  is  recognized  only  when  the 
protein  is  destroyed  by  heat  or  other  similar  agencies. 

When  a  solution  of  a  metallic  salt  comes  in  contact  with  a  living 
tissue,  such  as  the  mucous  membrane  of  the  mouth  or  stomach,  the 
same  precipitation  of  protein  and  metal  occurs  and  the  acid  is  liberated; 
the  local  action  appears  to  be  determined  by  the  combined  efl'ects  of 
these  factors.  _  The  more  completely  dissociated  the  ions  of  the 
salt  are,  the  more  rapid  is  the  reaction  with  protein,  and  the  more 
intense  the  local  action.  Thus  the  more  readily  ionized  inorganic 
salts  act  more  strongly  than  the  organic  ones,  which  are  slowly  disso- 
ciated, and  these  in  turn  are  more  liable  to  cause  marked  local  changes 
than  the  double  salts,  which  are  dissociated  with  difficulty.^  The 
actixity  of  the  acid  liberated  also  varies  with  the  extent  to  which  it  is 
dissociated  into  ions;  it  therefore  exercises  the  same  astringent  or 
corrosive  effects  as  if  it  had  been  a])])lied  imcombined,  but  its  action 
may  be  modified  by  the  presence  of  a  layer  of  i)recii)itate  i)rotecting  the 
surface.  Thus  when  a  weak  solution  of  lead  acetate  is  ap])lied  to  a 
mucous  membrane,  a  preci])itate  is  formed  in  the  ])roteins  lying  on  the 
surface,  and  ])rotects  tlie  cells  from  the  action  of  the  very  tlilute  acetic 
acid  which  is  set  at  liberty.  If  a  stronger  solution  be  applied,  howe\er, 
the  metallic  ]:)rccipitate  extends  into  the  cell,  while  tlie  acetic  acid,  being 
more  conc(>ntrate(l,  exercises  some  irritant  action.  As  the  concentration 
increases,  the  deeper  ])arts  of  the  ci)it]iclial  cells  are  coagulated,  and  at  the 
same  time  the  acid  becomes  more  destructive,  so  that  exentually  the 
superficial  layer  of  the  epithelhnn  is  killed  and  the  dei-jxT  layers  are 
attacked.  'J'he  acetate  of  lead  may  thus  act  as  an  astringent,  covering 
a  nnicous  surface  with  a  ])rotecti\e  ])ellicle  of  insoluble  i)rccii)itate, 

'  I'duli.  Bioclium.  Zoitschr.,  xli,  |).  401. 


HEAVY  METALS  613 

or  as  an  irritant,  which  in(hices  an  increase  in  the  circulation  of  the 
part,  a  more  rapid  division  of  the  cells  and  an  effusion  of  liquid,  or  as  a 
corrosive,  involving  the  superficial  layer  of  cells,  and  sometimes  even 
the  deeper  ones,  in  its  destructive  effects. 

^Yhen  the  nitrate  of  lead  is  applied,  the  astringent  effect  is  much 
less  evident,  the  irritant  and  corrosive  more  marked,  because  the  salt 
is  more  readily  dissociated  and  the  reaction  is  therefore  more  rapid, 
and,  in  addition,  the  nitric  acid  is  much  more  corrosive  than  acetic 
acid.  The  same  metal  attached  to  different  acids  may  therefore  induce 
very  different  effects,  in  the  one  case  acting  chiefly  as  an  astringent, 
in  the  other  as  an  irritant  and  corrosive. 

The  character  of  the  metal  which  is  carried  down  in  the  precipitate 
also  influences  the  local  effect;  thus  mercury  is  intensely  poisonous  and 
destroys  the  cells  in  which  it  is  deposited,  while  lead  is  a  less  powerful 
poison  and  the  cells  may  recover  even  if  lead  has  been  deposited  on 
them. 

In  addition,  salts  which  have  a  very  strong  affinity  for  water  with- 
draw fluid  from  the  cells,  and  thus  act  more  strongly  on  them  than 
others  which  have  not  this  character;  for  example  dried  alum  is  much 
more  destructive  to  the  tissues  with  which  it  comes  in  contact  than 
alum  containing  its  ordinary  water  of  crystallization. 

The  different  metallic  salts  therefore  vary  in  their  local  action  within 
wide  limits — from  the  formation  of  mildly  astringent  membranes  to 
the  production  of  widespread  necrosis  and  destruction  of  tissue. 

The  most  powerful  corrosive  salts  of  any  metal  are  those  which  are 
most  rapidly  dissociated  into  ions,  that  is,  the  chlorides  and  nitrates, 
provided  they  are  soluble.  The  sulphates  are  much  less  irritant,  because 
they  are  less  readily  dissociated,  and  perhaps  because  the  sulphuric 
acid  may  fail  to  penetrate  the  cells  owing  to  its  being  less  volatile 
and  its  anion  having  less  permeating  power  than  that  of  hydrochloric 
or  nitric  acid.  (See  page  101.)  The  iodides  and  bromides  are  generally 
regarded  as  less  irritant  than  the  chlorides,  but  are  less  frequently  used 
and  less  well  known. 

The  least  corrosive  of  the  salts  of  the  metals  are  those  formed  with 
the  slowly  dissociated  organic  acids,  such  as  the  acetates,  tartrates  or 
citrates.  When  these  are  united  with  a  metal  which  in  itself  is  not  a 
\ery  active  poison,  such  as  lead,  they  are  almost  purely  astringent. 
On  the  other  hand,  the  acetate  of  silver  or  of  mercury  tends  to  be 
irritant  and  corrosive,  from  the  poisonous  action  of  these  metals  on 
the  tissues.  In  any  case,  the  acetates  are  less  irritant  than  the  corre- 
sponding chlorides  and  nitrates,  provided  these  are  equally  soluble. 

The  local  action  also  varies  in  the  same  salt  of  different  metals. 
Lead  is  the  most  astringent  of  the  metals  ordinarily  used  in  solution, 
while  mercury  salts  have  little  or  no  astringent  action,  owing  to  their 
specific  poisonous  action  on  the  cells.  Iron  and  alum  approach  most 
nearly  to  lead,  then  copper,  zinc  and  silver,  and  at  a  longer  interval 
mercury  and  antimony. 

It  is  impossible  to  arrange  the  metallic  salts  as  either  astringents  or 


614  THE  HEAVY  METALS 

irritants,  because  in  every  instance  the  effect  varies  with  the  concen- 
tration, and  with  many  other  features,  such  as  the  condition  of  the 
surface  to  which  they  are  appHed,  and  the  quantity  of  protein  with 
which  they  come  in  contact  before  they  reach  the  Hving  membrane. 

Of  the  salts  in  common  use,  the  most  astringent  are  lead  acetate 
and  alum;  the  most  irritant  are  the  percliloride  and  the  nitrate  of 
mercury,  the  chlorides  of  zinc,  copper,  tin  and  antimon}^  while  the 
chlorides  of  iron,  sulphates  of  copper,  zinc,  iron  and  manganese,  the 
acetates  of  copper  and  zinc,  and  the  nitrates  of  silver  and  lead  are 
astringents  when  applied  in  very  dilute  solution,  but  tend  to  irritate 
and  corrode  in  large  quantities.  In  most  cases  the  effects  of  the  last 
group  are  made  up  of  a  mixture  of  astringent  and  irritant  action. 

The  insoluble  salts  come  into  less  intimate  contact  with  the  tissues, 
and  have  much  less  effect;  but  many  of  them  are  slowly  taken  up 
and  may  then  act  as  irritants  or  astringents. 

The  insoluble  preparations  of  mercury  tend  to  irritate  and  corrode 
the  surfaces  to  which  they  are  applied,  but  the  insoluble  salts  of  the 
other  metals  are  generally  astringent.  It  is  difficidt  to  determine 
how  far  the  so-called  astringent  and  protective  action  of  these  insoluble 
substances  is  due  to  the  formation  of  precipitates,  and  how  far  to  their 
acting  mechanically  as  protective  coverings  over  irritated  surfaces,  but 
the  latter  factor  is  undoubtedly  the  more  important  in  many  instances. 

If  the  metal  is  applied  in  the  form  of  an  "albuminate,"  that  is,  in  the 
protein  precipitate,  the  effects  are  the  same  as  if  it  were  used  in  any 
other  insoluble  form;  for  example,  lead  and  most  metals  cause  no 
irritation,  but  mercury  acts  as  an  irritant. 

The  precipitation  induced  by  the  astringents  involves  only  the  sur- 
face layer  of  cells,  l)ut  the  membrane  formed  protects  the  i)art  from 
mehanical  and  chemical  irritation,  and  thus  lessens  congestion  and 
inflammation.  Some  authors  maintain  that  the  astringents  contract 
the  vessels  by  direct  action  on  their  coals,  or  lessen  secretion  by  direct 
action  on  the  secretor\'  cells,  but  these  statements  are  not  satisfactorily 
established,  and  the  changes  may  be  the  indirect  results  of  the  i)ro- 
tectjon  afforded  to  the  surface  cells.  When  irritation  is  induced,  the 
vessels  of  course  dilate,  and  congestion  and  exudation  follow. 

The  salts  of  the  heavy  metals  are  often  only  slowly  Absorbed.  ]\ler- 
cury  is  again  an  excei)tion,  but  even  mercury  does  not  induce  general 
symptoms  imtil  many  hours  after  its  administration.  The  other  metals 
given  by  the  mouth  pass  through  the  alimentary  canal  for  the  most 
part  unabsorbed.  In  recent  years  it  has  been  disputed  whether  iron, 
manganese,  copper  and  other  metals  are  absorbed  at  all,  but  investiga- 
tion with  more  accurate  methods  has  shown  that  iron  and  manganese 
pass  into  the  tissues  from  the  aUmcntary  tract,  and  it  seems  j^robable 
that  a  small  proportion  of  most  of  the  metals  finds  its  way  into  the 
blood.  At  the  same  time  there  is  no  question  that  the  great  i)roportion 
of  most  of  the  metals  ])asses  through  una))sorbcd,  and  is  devoid  of  any 
effect  exce])t  from  its  local  action,  'i'lic  form  in  whicii  the  metals  arc 
absorbed  is  (juitc  unknown,  but  it  is  not  niilikclx   tliat  tlicy  arc  taken 


HEAVY  METALS  01;") 

up  in  insoluble  forms  by  the  leucocytes  and  thus  carried  into  the  tissues. 
When  there  is  any  lesion  of  the  stomach  and  intestine,  and  particularly 
when  the  salt  induces  irritation  and  congestion  itself,  much  more  of  the 
metal  is  taken  up  than  by  the  normal  epithelium.  But  even  in  the  most 
favorable  circumstances  little  of  the  metal  is  absorbed,  and  in  acute 
poisoning  the  symptoms  arise  from  the  local  irritation  and  corrosion 
and  only  to  a  smaller  extent  from  the  general  action  of  the  metal. 

If  the  absor])tion  of  the  metals  is  slow,  their  Excretion  progresses 
even  more  gradually,  and  repeated  administration  leads  to  their  ac- 
ciunulation  in  the  tissues  and  thus  to  intoxication.  The  metal  seems 
to  leave  the  blood  very  rapidly,  and  to  become  stored  up  in  various 
organs,  chiefly  the  liver,  to  a  less  extent  the  spleen,  kidney,  and  bone 
marrow.  While  some  of  the  metal  is  deposited  in  the  liver  and  other 
organs,  another  part  is  excreted,  for  the  most  part  along  the  alimentary 
tract.  Thus  it  is  found  in  the  saliva  and  the  secretions  of  the  stomach 
and  small  intestine  and,  to  a  much  larger  extent,  in  the  ca?cimi  and 
in  the  large  bowel;  in  some  cases  the  excretion  is  limited  to  the  large 
bowel,  a  strict  line  of  demarcation  being  formed  by  the  ileo-csecal  valve. 
A  comparatively  small  amount  escapes  with  the  urine.  Some  metals 
have  been  detected  in  very  small  quantity  in  the  milk,  and  there  is 
reason  to  suppose  that  traces  are  eliminated  by  the  other  cutaneous 
secretions. 

The  General  Action  of  the  heavy  metals  in  man  is  often  elicited 
only  by  their  prolonged  ingestion,  but  it  has  been  studied  in  animals 
by  the  intravenous  or  subcutaneous  injection  of  such  preparations  as  the 
double  salts,  which  do  not  precipitate  the  proteins  and  slowly  liberate 
the  metal  or  its  oxide.  The  ordinary  salts  cannot  be  used,  because  the 
precipitated  albumin  of  the  blood  causes  embolism,  and  this  obscures 
the  symptoms.  The  symptoms  of  acute  metallic  poisoning  elicited  thus 
in  animals  generally  resemble  fairly  closely  those  of  chronic  poisoning 
in  man. 

Even  when  the  heavy  metals  are  injected  into  the  blood  in  consider- 
able quantity,  the  symptoms  are  often  late  in  appearing,  in  the  case  of 
aluminium  only  after  several  days,  so  that  the  slowness  of  the  absorp- 
tion from  the  intestine  is  not  the  only  factor  in  the  delay  in  the  onset 
of  the  intoxication. 

The  general  symptoms  of  metallic  poisoning,  as  distinguished  from 
those  due  to  the  local  action  at  the  point  of  application,  arise  chiefly 
from  the  central  nervous  system,  and  from  the  excretory  passages — ■ 
the  alimentary  canal  and  the  kidney.  Metallic  poisoning  always 
induces  disturbance  of  the  Stomach  and  Intestine,  manifested  by  loss  of 
appetite,  pain  and  discomfort  in  the  abdomen,  nausea,  vomiting,  and 
purging.  In  some  cases  no  lesion  of  the  canal  is  observed  post  mortem, 
but  in  the  great  majority  congestion  and  swelling  of  the  mucous  mem- 
branes of  the  stomach  and  intestine  is  seen,  or  the  whole  surface  may  be 
covered  by  a  diphtheritic  membrane  composed  of  necrosed  cells  and 
inflammatory  exudate.  Beneath  this,  htemorrhages  occur,  and  if  the 
animal  live  long  enough,  ulcers  are  formed,  so  that  the  whole  condition 


Gl()  THE  HEAVY   METALS 

can  scarcoly  })c  distiuguishcd  from  that  of  (lyseiitcry.  Some  metals 
act  stroiijily  on  the  mouth  and  induce  reflex  saUvation,  wliicli  is  one  of 
tlH>  earliest  features  of  mercury  ])oisonin<2;.  The  linint;  memhraue  of  the 
mouth  becomes  congested  and  inflamed,  and  numerous  shallow  ulcers 
are  formed  in  it. 

The  heavy  metals  thus  seem  to  have  a  specific  action  along  the 
alimentary  tract  quite  indei)endent  of  the  local  action  induced  when 
they  are  swallowed,  and  a])i)arently  arising  from  their  excretion  along 
it.  One  or  two  metals,  notably  lead,  cause  c()nstii)atioii  and  colic  when 
they  are  absorbed  into  the  blood,  but  under  certain  circumstances  they 
too  induce  purgation. 

Another  organ  which  sufl'ers  from  the  circulation  of  metals  in  the 
blood  is  the  Kidney.  (\)m])aratively  little  of  the  metal  is  excreted  in 
the  urine,  but  it  is  found  that  most  of  this  class  act  as  diuretics^  in 
small  quantities.  Somewhat  larger  doses  irritate  the  renal  epithelium, 
and  albumin  ai)i)ears  in  the  urine,  along  with  casts,  and,  in  severe 
cases,  blood  cells  and  hainoglobin.  If  this  irritation  of  the  secretory 
cells  l)e  long  continued,  it  sets  up  a  secondary  inflammation  of  the 
interstitial  tissue,  and  cirrhosis  of  the  kidney  results. 

The  Circulation  is  dift'erently  aft'ected  by  dift'erent  metals.  The 
heart  is  often  weakened  only  in  the  last  stages,  and  it  is  imi)ossible  to 
determine  how  far  its  failure  is  due  to  direct  action,  and  how  far  to 
the  disorder  of  the  nutrition.  The  blood-pressure  invariably  falls 
toward  the  fatal  issue  of  the  intoxication,  and  as  a  general  rule,  a 
slow  fall  in  observed  from  the  beginning.  This  fall  in  blootl-pressure 
may  doubtless  l)e  induced  by  dift'erent  fai-tors  in  the  dift'erent  forms 
of  intoxication,  but  there  is  no  question  that  it  is  })artly  due  to  the 
dilatation  of  the  vessels  of  the  intestines  and  stomach  from  the  inflam- 
mation of  these  organs.  In  acute  general  poisoning  in  animals,  many 
of  the  metals  cause  a  great  fall  of  blood-i^ressure,  which  has  been  ascribed 
to  their  paralyzing  the  walls  of  the  smaller  arterioles  and  capillaries. 

The  general  malnutrition  from  the  gastro-intestinal  action  renders  it 
impossible  to  determine  whether  the  metals  alter  the  metabolism  of  the 
body  through  directly  afl'ecting  the  cells,  but  it  is  not  improbable  that 
this  is  the  case,  for  tlie  loss  of  weight  is  often  too  rapid  to  be  exi)lainctl 
by  the  star\ation  alone. 

The  Central  Nervous  System  is  always  aft'ected  more  or  less  by  the 
presence  of  the  metals  in  the  l)lood.  As  a  general  rule,  the  symptoms 
are  a  mixture  of  those  of  stinuflation  of  certain  divisions  with  those  of 
paralysis  of  others.  Several  metals  induce  disturbance  of  the  psychical 
centres,  manifested  in  delirium,  halhicinations  and  mania,  or  ui  stui)or 
and  coma.  Convulsions  of  all  forms  uulicate  that  the  motor  areas  of 
the  brain,  the  basal  ganglia  and  the  spinal  cord  arc  alfcctcd;  thus 
epileptiform  ( onx  ulsions,  chorea,  clonic  and  tonic  si)asms  occur  from 
metallic  jioisoning.  In  several  instances  actual  lesions  of  the  brain  cells 
hiiNcbccn  shown  to  be  caused  by  the  ingestion  of  the  metals.  They 
often  cause  general  weakness,  or  i)aresis  of  certain  groups  of  nuiscles, 
and  in  addition  to  their  speciflc  action  on  the  ncr\()us  centres,  they  may 
induce  |:cri|»hcral  neuritis  (lead). 


HEAVY  METALS  017 

Therapeutic  Uses. — In  therapeutics  only  mercury  and  iron  are  lar<>cly 
employed  for  their  effects  after  al)sor])tion,  while  the  others  ha\e  a 
more  or  less  extensive  use  for  their  local  effects  as  astrinj^ents,  irritants, 
caustics  or  styptics.  Iron  is  not  prescribed  for  its  general  action  on 
the  organs,  Init  to  supi)ly  the  phce  of  food-irons  in  the  formation  of 
haemoglobin.  Mercury  is  used  for  its  specific  effect  in  syi)hilis,  and  some 
of  its  preparations  have  been  advised  as  diuretics.  Not  infrequently 
the  local  action  of  the  heavy  metals  is  supposed  to  be  induced  after 
absorption,  and  prescriptions  are  met  with  containing  lead  or  iron  which 
are  intended  to  stay  haemorrhage  from  the  lungs  or  from  the  kidneys. 
It  ought  to  be  recognized,  however,  that  lead  or  iron  is  al)soibed  only 
in  minute  quantities,  and  that  they  have  no  predilection  for  the  bleeding 
points.  If  they  were  capable  of  coagulating  the  blood  after  absorption, 
and  thus  stopping  luvmorrhage,  they  would  certainly  do  so  in  the 
portal  circulation  and  would  not  be  carried  to  the  limgs  or  kidney  before 
they  acted.  x\s  a  matter  of  fact,  howe^■e^,  they  never  reach  the  blood 
except  in  forms  in  which  they  have  no  astringent  or  styptic  action. 

]Many  of  the  metallic  salts  are  powerful  disinfectants,  partly  no 
doubt  from  their  coagulating  the  proteins  of  the  microbes,  but  also 
from  a  specific  poisonous  action  on  them,  which  is  quite  distinct  from 
their  precipitating  action.  As  a  general  rule  the  disinfectant  power 
varies  with  the  degree  of  dissociation  of  the.  salt,  that  is,  with  the 
nimiber  of  metallic  ions  present  in  the  solutions,  although  the  undisso- 
ciated  molecule  also  seems  to  have  some  influence,  and  a  salt  which  is 
dissociated  with  difficulty  may  in  some  instances  make  up  for  this 
drawback  by  the  more  intense  toxicity  of  the  metal. ^  The  most  widely 
used  metallic  antiseptics  are  the  mercurial  salts,  in  particular  the 
perchloride,  but  silver  is  used  as  a  disinfectant  in  some  diseases  and 
copper  has  been  suggested. 

Almost  incredibly  small  quantities  of  some  of  the  metals  have  been 
found  to  be  rapidly  fatal  to  some  of  the  alga^,  the  bacteria,  and  the 
infusoria.  Thus  one  part  of  the  perchloride  of  mercury  in  one  million 
parts  of  water  kills  spirogyra,  one  of  the  simpler  alga^,  and  water  dis- 
tilled from  copper  vessels  or  in  which  small  pieces  of  copper  foil  have 
been  suspended-  is  rapidly  destructive  to  many  lower  organisms.  Silver 
is  less  active  and  lead  still  less  so.  The  amount  of  copper  in  the  solution 
is  too  small  to  be  recognized  by  any  chemical  test.  These  results,  which 
were  first  obtahied  by  Xaegeli,  and  which  have  been  confirmed  by  other 
observers  besides  Israel  and  Klingmann,  indicate  that  certain  lower 
organisms  are  much  more  sensiti\'e  to  the  action  of  copper,  and  probably 
of  other  metals,  than  the  more  highly  organized  plants  and  animals. 
Further  examination  of  their  effects  as  disinfectants  in  medicine  and 
surgery  is  certainly  desirable.  Other  curious  effects  on  the  growth  of 
bacteria  have  been  observed  by  Bolton  and  Brown,^  who  found  that  a 
piece  of  metal  placed  on  a  culture  of  microbes  in  gelatin  causes  curious 

1  Kronig  u.  Paul      Ztschr.  f.  Hygiene,  xxv,  p.  1. 

2  Israel  u.  Klingmann.     Virchows  Arch.,  cxlvii,  p.  293. 

3  Transactions  uf  the  Assoc,  of  Amer.  Physicians,  xii,  p.  488. 


CIS  THE  HEAVY  METALS 

alternating  zones  of  intense  growtli  and  of  sterility.  These  observa- 
tions have  recently  been  extended  by  Thiele  and  WoJflV  who  state 
that  silver,  mercury,  or  copper  plates  prevent  the  growth  of  microbes 
owing  to  niiinite  traces  of  these  metals  being  dissolved  in  the  medium. 
Se^•e^al  other  hea^■y  metals^ron,  lead,  zinc,  tin,  gold,  platinum  and 
aluminimi — proved  devoid  of  action.  A  practical  application  of  this 
bactericidal  action  of  the  metals  has  been  made  by  the  introduction  of 
solutions  of  colloid  forms  of  silver  and  mercury  as  antise])tics.  Some 
of  these  colloid  metals  have  proved  destructiNe  to  sini})le  organisms  in 
extremely  dilute  solution,  while  in  more  concentrated  forms  they  are 
inferior  to  the  ordinary  salts  of  the  metals;  there  is  every  reason  to 
believe  that  these  colloid  forms  like  the  ordinary  pure  metals  have  no 
action  until  they  are  changed  to  dissociable  salts,  which  exert  their 
usual  cH'ccts  in  the  tissues. 

I.    ANTIMONY. 

The  preparations  of  antimony  played  a  much  more  important  role 
in  therapeutics  in  the  earlier  part  of  last  century  than  at  tlie  present 
time.  In  many  respects  they  resemble  arsenic  in  their  effects,  and 
may  be  looked  upon  as  forming  a  link  between  it  and  the  salts  of  the 
other  heavy  metals.  The  salt  most  commonly  used  is  tartur  emetic, 
or  the  double  tartrate  of  antimony  and  potassium  (K(SbO)C4H406). 
The  effects  of  this  salt  were  at  one  time  believed  to  be  due  in  part  to 
the  potassium,  but  have  been  shown  to  be  those  of  the  antimony  alone. 
As  a  double  salt  it  is  not  readily  dissociated  and  is  therefore  not  so 
corrosive  as  the  chloride,  which  is  a  powerful  caustic  when  apj^lied  to 
the  skin  or  the  mucous  membranes. 

When  rubbed  on  the  Skin,  however,  tartar  emetic  causes  redness, 
and  a  papular  eruption,  which  later  passes  into  vesicles  and  pustules. 
If  the  application  be  further  persisted  in,  these  pustules  may  become 
confluent  and  form  small  abscesses,  and  later  cause  extensive  necrosis 
and  ulceration  of  the  skin.  The  points  of  origin  of  the  papules  are 
the  openmgs  of  the  cutaneous  glands  and  the  hair  follicles.  When 
injected  hypodermically,  tartar  emetic  causes  intense  and  lasting  pain, 
and  very  often  suppuration  and  sloughing,  which  may  imohe  the 
underlying  nmscles. 

Symptoms. — Tartar  emetic  has  a  slight,  acrid  taste,  and  in  very  small 
quantities  causes  no  symptoms,  except  some  perspiration.  In  somewhat 
larger  doses  its  ingestion  is  followed  by  nausea  and  vomiting,  with 
very  marked  depression  and  the  usual  accompaniments  of  emesis,  such 
as  salivation,  ])rofuse  perspiration  and  acceleration  of  the  pulse  (see 
A})omori)liine,  ])age  4134).  In  antimonial  i)oisoning  the  vomiting  is 
violent  and  continuous,  the  ordinary  contents  of  the  stomach  being 
first  ('\acuated,  and  then  a  slimy  mucous  fluid,  which  may  later  contain 
blood.    In  some  cases  it  is  said  that  no  gastric  symptoms  are  observed, 

'  Arcli.  f.  Hygiene,  xxxiv,  p.  43.  Foa  (ind  A(nin:otti.  Bioclicin.  Ztsdir.,  xix  Moore 
and  llawk.      liiocliciii.  Joiirii.,  iii,  p.  '.M\i. 


ANTIMONY  CI  9 

but  these  must  be  exceedingly  rare.  The  vomiting  is  accompanied 
by  profuse  watery  diarrhoea,  resembling  that  of  arsenical  poisoning, 
and  by  great  muscular  weakness  and  collapse.  The  pulse  may  be 
somewhat  accelerated  at  first,  but  is  weak,  and  later  becomes  slow  and 
irregular.  The  skin  is  cold  and  covered  with  clammy  i)erspiration, 
and  cyanosis  of  the  face  and  extremities  is  generally  marked.  The 
respiration  is  slow  and  may  be  irregular,  the  voice  weak  and  husky, 
the  temperature  is  depressed,  and  the  patient  falls  into  a  comatose  con- 
dition, which  deej^ens,  until  after  a  few  weak  convulsive  movements  the 
respiration  ceases.  The  urine  is  sometimes  increased  in  the  beginning 
of  the  poisoning,  but  later  may  become  scant}'  or  entirely  suppressed. 
It  often  contains  albumin. 

The  minimum  fatal  dose  of  tartar  emetic  is  doubtful,  as  the  greater 
part  of  the  poison  is  generally  removed  by  vomiting.  Recovery  has 
been  observed  after  very  large  quantities,  while  in  other  cases  0.1  G. 
(2  grs.)  has  proved  fatal. 

Chronic  antimoiiial  poisoning  is  very  rare  and  difficult  to  diagnose.  The 
symptoms  are  depression,  headache,  giddiness  and  confusion,  drowsiness  and 
indistinct  sight.  The  appetite  is  bad,  and  the  patient  complains  of  heavhiess, 
discomfort  or  pain  in  the  region  of  the  stomach,  general  weakness  and  exhaus- 
tion. Profuse  diarrhoea  may  be  present,  rapid  loss  of  flesh,  albuminuria,  and 
finally  collapse.  Pustular  eruptions  have  been  observed  from  the  prolonged 
internal  use  of  tartar  emetic.  There  is  some  reason  to  suppose  that  printers 
occasionally  suffer  from  antimony  poisoning  arising  from  the  presence  of  anti- 
mony in  the  types. 

Action. — Many  of  the  symptoms  of  antimonial  poisoning,  the  profuse 
perspiration,  salivation  and,  to  some  extent  at  least,  the  collapse, 
are  manifestly  secondary  to  the  Emetic  Action,  and  the  cause  of  the 
vomiting  has,  accordingly,  been  repeatedly  investigated.  The  older 
writers  regarded  it  as  arising  from  some  central  action,  but  there  can 
be  no  question  that  it  is  the  result  of  local  irritation  of  the  stomach; 
small  quantities  cause  vomiting  without  any  obvious  lesion,  but  larger 
doses  induce  hypersemia  and  swelling  of  the  gastric  mucous  membrane. 
Large  quantities  of  antimony  injected  intravenously  or  subcutaneously 
also  cause  vomiting  and  purging,  from  the  metal  being  excreted  into  the 
stomach  and  bowel  and  thus  causing  irritation;  but  much  smaller 
ciuantities  suffice  to  cause  vomiting  when  given  by  the  mouth. 

In  the  stomach  the  antimony  is  slowly  dissociated  from  the  double 
salt  and  acts  as  an  irritant;  this  liberation  of  the  antimony  ion  may  be 
aided  by  the  acid  reaction,  but  it  also  occurs  when  the  reaction  is  rendered 
neutral,  and  in  the  intestine  and  skin  where  the  reaction  is  not  acid. 
It  is  more  irritant  than  arsenic  and  is  absorbed  more  slowly,  so  that  its 
action  remains  confined  to  the  stomach,  and  as  the  \omiting  removes 
much  the  greater  part  of  the  poison,  the  intestine  remains  unharmed 
except  when  large  quantities  have  been  swallowed  and  the  emesis  is 
from  any  cause  insufficient.  In  chronic  poisoning  ulceration  of  the 
small  intestine  is  said  to  occur,  especially  around  the  solitary  follicles- 
and  Peyer's  patches. 


f)20  THE  HEAVY  METALS 

The  acceleration  of  the  Pulse  seen  after  tartar  emetic  is  due  to  the  emetic 
action  and  not  to  the  al)sor])tion  of  the  (h-ug.  When  injected  into  a  vein  in 
animals,  antimony  acts  directly  on  the  cardiac  muscle  and  causes  a  slow  and 
weak  pvdse,  although  this  is  ])roccded  in  some  cases  l)y  slight  acceleration. 

The  Blood-pressure  falls  throujihout  the  experiment,  parti}'  omng  to  the 
weakness  of  the  heart,  but  chiefly  owing  to  an  action  on  the  vascular  mech- 
anism similar  to  that  described  under  arsenic. 

The  Respiration  is  often  slightly  accelerated  at  first,  anrl  maj^  be  shallow 
and  irregular  from  the  nausea;  Init  in  cases  of  poisoning  it  becomes  slow  and 
labored,  and  eventually  ceases  along  with  the  heart.  Marked  congestion  and 
anlema  of  the  lungs  is  often  found  in  fatal  poisoning. 

The  Central  Nervous  System  is  depressed  by  antimony  in  the  frog,  while 
its  effects  in  mammals  are  more  obscure,  for  it  is  impossible  to  ascertain  how  far 
the  changes  are  due  to  direct  action  and  how  far  they  are  attributable  to  the 
disturbance  of  the  circulation  and  the  alimentary  canal.  There  is  reason  to 
believe,  however,  that  the  poison  depresses  to  some  extent  th(!  nerve  cells  here 
also.  According  to  Schaffer,  tlu;  cells  of  the  spinal  cord  undergo  a  degeneration 
marked  by  the  disappearance  of  the  chromatin  in  chronic  antimonial  poisoning. 

The  Depression  and  Collapse  of  antimony  poisoning  are  caused  by  the 
gastric  effects  and  the  slowed  circulation  acting  on  the  central  nervous  system, 
and  not,  as  is  sometimes  stated,  by  the  peripheral  nerves  and  muscles  being 
affected.  The  voluntary  muscular  tissue  is  undoubtedl.y  weakened  to  some 
extent  in  the  frog,  but  only  after  large  doses  and  at  a  late  stage.  The  muscles 
then  contract  somewhat  more  weakly  than  normally,  and  are  more  readily 
fatigued. 

Many  of  the  Secretions  are  increased  by  tartar  emetic,  such  as  the  perspi- 
ration, the  saliva  and  the  mucous  secretion  of  the  respiratory  tract.  This  is 
not  due  to  any  direct  action  on  the  glands,  for  the  same  effect  is  induced  by 
anything  which  causes  vomiting.  (See  Apomorphine,  page  434).  The  urine 
is  sometimes  increased  by  antimony,  at  other  times  it  is  diminished  or  sup- 
pressed. This  indicates  that  antimony,  like  most  of  the  heavy  metals,  irritates 
the  kidneys  and  thus  increases  their  activity  in  small  doses,  while  larger  amounts 
cause  inflammation  and  albuminui'ia  or  anuria;  acute  nephritis  with  ha>mor- 
rhages  is  often  found  in  fatal  poisoning. 

The  irritant  action  of  tartar  emetic  on  the  Skin  when  it  is  ai)plied  to  it  in 
ointment  arises  from  the  liberation  of  the  antimony  from  the  double  salt; 
this  ai)parently  fails  to  penetrate  through  the  horny  epidermal  layer  and  thus 
only  causes  irritation  where  it  reaches  the  unprotected  living  cells  at  the  mouths 
of  the  glands.  The  inflammation  thus  occurs  at  discrete  points  which  may 
supi)Ui'ate  and  form  pustules. 

Antimony  is  nuich  less  poisonous  than  arsenic  to  most  of  the  protozoa,  but 
is  found  to  possess  the  same  extraordinary  affinity  for  certain  pathogenic 
organisms,  notably  the  trypanosomes  of  tlu;  blood,  which  it  destroys  in  solutions 
as  weak  as  one  in  500,000. 

The  effe(;ts  of  antimony  on  the  Nutrition  have  not  been  so  carefully  examinetl 
as  those  of  arsenic,  but,  as  far  as  is  known,  i)resent  a  strong  resemblance  to 
them.  Thus  fatty  degeneration  of  many  organs  is  induced  by  its  jirolonged 
use,  the  nitrogen  of  the  urine  is  found  to  be  increased  and  the  glycogen  dis- 
api)ears  from  the  liver.  Very  small  quantities  of  antimony  given  repeatedly 
are  said  to  increase  the  glycogen  and  fat  of  the  liver,  without  ai)parcntly  altering 
the  nitrogen  of  the  urine. 

The  fall  in  Temperature  after  antimony  is  often  very  considerable,  amount- 
ing in  animals  to  ti°  C.  in  the  course  of  a  few  hours.  It  is  exi)lained  by  thC; 
slowness  of  the  circulation  and  by  the  general  depression  and  collapse  and 
profuse  i)erspiration. 

Antimony  is  Absorbed  fioin  the  skin  very  slowly,  and  from  the  stomach 
and  intestine,  ll  |)asse.s  into  the  tissues  nmch  more  gradually  than  arsenic, 
liowexci-,   and   its  action   on   the  stomach   can,   therefore,   be  elicited  without 


ANTIMONY  621 

(hmgcr  of  its  causinj;-  <i;eucral  syinploiiis.  Al'Icr  aljsorptioii  aiitiinony  is  I'oiiml 
in  considerable  quantity  in  the  liver,  which  stores  it  up  for  some  time.  It  is 
excreted  into  the  stomach  and  intestine,  in  the  urine,  and,  it  is  said,  in  the  bile 
antl  milk.  No  such  tolerance  is  acquired  for  antimony  as  is  observed  under 
arsenic. 

The  Chloride  of  Antimony  (SbCb)  differs  from  tartar  emetic  chiefly  m  bcuig 
a  violent  corrosi\e,  owing  to  the  readiness  with  which  the  antimony  ion  is 
freed  from  it.  The  other  compounds  of  antimony  act  like  the  double  tartrate, 
except  that  most  of  them  are  much  slower  in  their  effects.  Stibine,  or  anti- 
moniurettcd  hydrogen  (SbHs),  differs  entirely  from  arsine  (AsHs)  in  its  action, 
which  is,  however,  equally  poisonous.  It  has  very  rarely  been  examined, 
except  in  an  impure  form,  and  the  symptoms  are  imperfectly  known. 

Preparations. 

Antimonii  et  PoTASsii  Tartras  (U.  S.  p.),  Antimonium  Tartaratum 
(B.  p.),  iartar  emetic,  tartrated  antimony  (  (KSbOC4H406)2  +  H2O),  forms 
colorless,  transparent  crystals,  or  a  white  granulated  powder,  without  odor, 
and  having  a  sweet,  afterward  disagreeable,  metallic  taste,  soluble  in  17  parts 
of  cold  water,  insoluble  in  alcohol.  Dose  as  an  expectorant,  0.005  G.  (xV  gr-) 
as  an  emetic,  0.03  G.  {\  gr.);  B.  P.,  expectorant,  jV-i  gr.;  emetic,  |-1  gr 

ViNUM  Antimonii  (U.  S.  P.),  Vinum  Antimoniale  (B.  P.),  4  per  mille.  1  c.c. 
(15  mins.);  B.  P.,  10-30  mins.,  diaphoretic;   2-4  fl.  drs.,  emetic. 

Tartar  emetic  is  also  contained  in  the  compound  syrup  of  squills  U.  S.  P. 

Therapeutic  Uses. — Antimony  is  used  to  a  much  less  extent  in  medicine 
than  was  formerly  the  case.  In  the  seventeenth  century  it  was  pre- 
scribed so  widely  and  was  believed  to  do  so  much  harm,  that  the  gradu- 
ates in  medicine  of  Heidelberg  were  required  to  take  an  oath  never  to 
use  it.  At  present  it  is  used  to  a  limited  extent  as  an  emetic,  but  is 
slow  in  action  and  induces  greater  depression  and  more  prolonged 
nausea  than  the  other  drugs  which  are  prescribed  for  this  purpose, 
such  as  apomorphine,  ipecacuanha,  or  sulphate  of  copper.  It  is  therefore 
seldom  used  to  evacuate  the  stomach  in  cases  of  poisoning  or  of  foreign 
bodies  in  the  stomach  or  tesophagus.  Its  expectorant  action  is  taken 
advantage  of  in  acute  bronchitis  in  which  the  secretion  of  the  bronchial 
mucous  membrane  is  insufficient,  but  is  of  less  value  when  the  secretion 
is  abundant.  In  commencing  bronchitis  tartar  emetic  is  sometimes 
gi\en  until  Aomiting  occurs,  and  then  continued  in  smaller  doses  and 
at  longer  intervals.  It  has  recently  been  used  in  trypanosomiasis, 
especially  in  sleeping  sickness,  in  which  it  has  been  administered^  by 
the  mouith,  intravenously  and  hypodermically.  It  is  at  least  as  efficient 
as  the  arsenic  preparations,  but  its  use  is  limited  by  the  intense  local 
action,  which  i)recludes  its  subcutaneous  injection.  Other  protozoal 
diseases,  such  as  syphilis,  have  also  been  treated  with  it,  and  there  is 
every  probability  that  if  a  suitable  combination  could  be  formed  it 
would  equal  or  surpass  the  modern  arsenical  compounds  in  efficacy. 
It  was  formerly  given  along  with  mercury  in  Plummer's  pill. 

It  is  also  used  as  a  diaphoretic  to  some  extent  in  the  same  doses  as  are  pre- 
scribed as  expectorants,  but  it  has  been  almost  entirely  supplanted  by  pilo- 
carpine for  this  purpose. 


622  THE  HEAVY  METALS 

In  acuto  fever  antimony  was  formerly  largely  used  as  a  depressant,  more 
especially  wlien  delirium  was  a  marked  feature.  The  object  was  to  produce 
a  mild  collapse,  but  the  treatment  has  been  entirely  abandoned  liy  most  author- 
ities, and  prol)ably  did  more  harm  than  good.  Acute  lobar  pneumonia  was 
ahnost  universally  treated  by  tartar  emetic  at  one  time,  and  an  attempt  has 
recently  been  made  to  revive  this  treatment  but  without  success. 

Antimony  has  been  advised  instead  of  arsenic  in  the  internal  treatment  of 
skin  disease,  but  it  is  impossible  to  state  at  present  how  far  it  is  capable  of 
replacing  the  more  widely  used  drug. 

In  all  cases  in  which  there  is  marked  depression  or  weakness,  in  which  the 
stomach  or  bowel  is  disordered,  or  in  which  the  circulation  is  feeble,  the  pre- 
parations of  antimony  are  contraindicated. 

Tartar  emetic  was  formerly  used  in  ointnient  (one  part  to  four)  as  a  skm 
irritant,  but  its  continued  application  has  led  in  several  cases  to  diffuse  sub- 
cutaneous abscess,  and  sometimes  to  necrosis  of  bone,  so  that  the  tartar  emetic 
ointment  has  passed  into  desuetude. 

In  cases  of  Antimonial  Poisoning,  emetics  are  seldom  required,  but 
the  stomach  may  be  washed  out  by  means  of  the  stomach  tube,  if 
\-omiting  is  not  present,  and  a  purge  may  be  given  to  remove  the  poison 
in  the  bowel.  Tannic  acid,  lime  or  magnesia  may  be  used  to  preci])itatc 
the  antimony  in  the  stomach,  and  potassium  hexatantalate  has  recently 
been  advised  for  this  purpose. 

Bibliography. 

Ackermann.     Virchow's  Arch.,  xxv,  p.  531. 
Radziejewski.     Arch.  f.  Anat.  u.  Phys.,  1871,  p.  472. 
Saikowski.     Virchow's  Arch.,  xxxiv,  p.  73. 
Soloweitschyk.     Arch.  f.  exp.  Path.  u.  Pharin.,  xii,  p.  438. 
Ringer  and  Murrell.     Journ.  of  Physiol.,  i,  p.  241. 

Chittenden  and  Blake.  Studies  from  the  Lab.  of  Physiolog.  Chom.,  Sheffield  Scientific 
School,  ii,  p.  87;    iii,  p.  106. 

Kubeler.     Arch.  f.  exp.  Path.  u.  Pharin.,  xxvii,  p.  451. 
Thomson  and  Cushny.     Proc.  Royal  Society,  B.,  Ixxxii,  p.  249. 
Rowntree  and  Abel.     Journ.  of  Pharmacology,  ii,  p.  101. 
Cloetta.     Arch.  f.  exp.  Path.,  Ixiv,  p.  352. 

n.     MERCURY. 

Mercury,  one  of  the  most  jjowerful  inorganic  i)ois()ns,  has  been  used 
in  medicine  for  a  long  time  and  in  a  large  variety  of  forms.  Some 
diflerences  are  observed  in  the  action  of  these,  but  all  of  them  induce 
the  same  general  results,  the  difi'eronces  existing  only  in  their  local 
effects,  and  being  due  to  the  salts  dill'cring  in  solubility  and  dissocia- 
bility.  A  soluble  salt,  such  as  the  perchloride,  comes  into  more  intinuite 
contact  with  the  tissues,  and  therefore  acts  more  powerfully  locall\- 
and  is  also  absorbed  more  rapidly  and  in  larger  amount  than  calomel, 
which  is  entirely  insoluble  in  water.  Both  the  local  and  the  general 
ellectsof  the  ])erchl()ride  are  more  marked  than  those  of  calomel,  tliere- 
fore,  but  when  sufficient  mercury  in  the  form  of  calomel  is  absorbed 
into  the  tissues,  the  general  eflects  are  the  same  as  if  an  e(iuai  quantity 
liad  been  taken  up  as  jjerchloride. 

The  corrosive  action  of  the  solul)le  mercury  salts  is  doubtless  due 
in  part  to  their  i)recii)itation  of  the  proteins,  but  in  addition  to  this  there 


MERCURY  623 

is  a  specific  toxic  action  on  all  living  c-ells.  It  is  unknown  in  what  form 
mercury  is  absorbed  and  circulates  in  the  blood,  but  there  is  no  evidence 
that  the  insoluble  preparations,  such  as  calomel,  are  changed  to  the 
soluble  perchloride  before  absorption;  on  the  contrary,  the  mercury  of 
the  perchloride  is  precipitated  in  contact  with  proteins  and  must  be 
taken  up  in  this  insoluble  form.  When  mercurj^  is  injected  hypo- 
dermically  in  an  insoluble  form,  the  leucocytes  take  it  up  and  carry  it 
off  as  they  do  any  other  foreign  insoluble  body,  and  it  is  quite  possible 
that  they  may  take  it  up  in  the  same  way  from  the  alimentary  canal. 
Less  of  the  insoluble  preparations  are  absorbed  merely  because  they 
come  into  less  intimate  contact  with  the  tissues  than  the  soluble  per- 
chloride; but  even  the  metal  may  be  oxidized  and  absorbed  when  it  is 
applied  to  the  li^•ing  surfaces  or  injected  into  the  blood  in  a  state  of 
fine  division.  Thus  the  inhalation  of  mercury  vapor  by  the  lungs  leads 
to  general  poisoning,  often  of  a  very  malignant  type,  and  mercury 
rubbed  into  very  fine  globules,  and  applied  in  ointment  to  the  skin, 
passes  into  the  gland  ducts  and  along  the  roots  of  the  hairs,  and  is 
absorbed  into  the  tissues,  in  which  it  causes  the  typical  mercurial 
effects. 

Symptoms. — Acute  Mercurial  Poisoning  occiu-s  only  from  the  use  of 
soluble  preparations,  and  in  particular  from  the  perchloride  of  mer- 
cury, or  corrosive  sublimate.  ]Many  cases  have  arisen  from  this  poison 
being  swallowed  accidentally  or  with  suicidal  intent,  or  from  its  use 
as  a  disinfectant  A\ash  for  large  cavities.  When  corrosive  sublimate 
is  swallowed  in  poisonous  quantity,  the  patient  complains  at  once 
of  the  harsh  metallic  taste,  which  is  followed  by  burning  pain  in  the 
mouth,  throat,  and  stomach.  Nausea  and  vomiting  set  in  very  soon, 
and  the  vomited  matter  may  contain  shreds  of  mucous  membrane  and 
blood.  Diarrhoea  and  violent  tenesmus,  with  watery  or  bloody  stools, 
often  containing  shreds  of  membrane,  may  be  among  the  early  symp- 
toms, or  may  only  occur  after  twenty-four  hours.  These  symptoms 
from  the  alimentary  canal  are  accompanied  by  collapse,  with  a  small, 
thready,  sometimes  irregular,  pulse,  shallow,  irregular,  rapid  respiration, 
cold,  clammy  skin,  pinched  features,  and  sunken  eyes.  The  temperature 
is  often  sul)normal,  but  sometimes  fever  is  observed,  although  this  is 
attributed  by  many  to  concurrent  disease.  The  consciousness  is  usually 
unaffected,  but  in  some  cases  somnolence,  giddiness,  or  more  rarely 
anxiety  and  restlessness  have  been  observed.  The  urine  is  much  dimin- 
ished and  complete  anuria  often  occurs  in  a  few  hours.  If  the  urine 
is  not  completely  suppressed,  it  generally  contains  albumin,  renal 
epithelium,  casts  and  more  rarely  sugar.  Death  may  occur  within  an 
hour  from  shock,  but  more  frequently  the  patient  survives  several  days 
or  even  one  or  two  weeks,  the  symptoms  of  intestinal  corrosion  and  of 
renal  irritation  continuing,  until  he  finally  sinks  from  exhaustion. 

When  acute  poisoning  occurs  from  the  absorption  of  corrosive  sub- 
limate from  wounds,  the  symptoms  of  corrosion  of  the  mouth  and 
stomach  are  absent  at  first,  but  the  dysenteric  symptoms  and  the  renal 
inflammation  are  produced  in  the  same  way  as  when  the  poison  is 


624  TUK   HEAVY   METALS 

swallowed.  Here  again  the  patient  may  die  within  a  few  honrs,  but 
more  frequently  survi\'es  for  several  days,  and  in  the  latter  case  the 
sym]itoms  toward  the  end  ])artake  of  the  character  of  chronic  poison- 
ing. In  particular,  sali\ation  and  stomatitis  set  in  in  the  course  of  a 
few  days.  These  also  occur  when  the  poison  is  swallowed,  although 
they  are  more  liable  to  be  overlooked,  from  the  cauterization  produced 
in  the  mouth  by  the  local  action. 

Chronic  Poisoning. — A  much  more  frequently  observed  form  of 
poisoning  is  that  induced  by  the  ])rolonged  medicinal  use  of  mercury. 
It  may  arise  from  any  of  the  preparations,  and  from  any  form  of  ap- 
plication, although  some  methods  of  administration  are  credited  with 
being  less  liable  to  induce  it  than  others.  Thus  inunction  with  mer- 
curial ointment  and  the  use  of  calomel  internally  are  both  more  liable 
to  cause  the  severer  forms  of  stomatitis  than  is  corrosive  sublimate. 
A  single  hypodermic  injection  of  an  insoluble  prei)aration  may  induce 
it  in  susceptible  persons,  because  the  mercury  is  only  slowly  absorbed, 
and  passes  into  the  tissues  as  gradually  as  if  it  were  given  by  the  mouth 
regularly  for  several  days.  This  chronic  poisoning,  or  Mercurialism,  is 
due,  not  to  the  local  action,  but  to  the  effects  of  the  drug  after  ab- 
sorption. It  may  follow  the  abuse  of  mercury  in  any  case,  but  some 
indi^•iduals  exhibit  a  sj^ecial  suscei)tibility  from  some  unknown  cause. 
P'ormerly  it  was  believed  that  the  earlier  symptoms  of  mercurial  ])oison- 
ing  had  to  be  induced  in  the  cure  of  syphilis,  but  in  modern  therapeutics 
every  effort  is  made  to  avoid  them.  The  first  symptoms  generally 
arise  from  the  month  and  throat,  the  patient  complaining  of  a  metallic 
taste,  and  of  a  feeling  of  numbness  or  soreness  of  the  tongue  and  gums. 
The  breath  has  an  unpleasant  foetid  odor,  the  tongue  is  swollen  and 
thickly  coated,  the  gums  are  soft,  swollen  and  often  of  a  dark  bluish-red 
or  gray  color  and  the  flow  of  saliva  is  augmented.  If  the  medication  be 
continued,  as  was  often  done  formerly,  ulcers  appear  on  the  gums  and 
on  the  sides  of  the  tongue  Avhere  it  comes  in  contact  with  the  teeth, 
especially  if  these  are  carious,  and  on  the  mucous  membrane  of  the 
cheeks;  the  salivation  increases  and  irritates  the  lips  and  the  skin  where 
it  is  exposed  to  the  secretion.  If  the  administration  of  mercury  be  still 
l)ersisted  in,  the  teeth  become  loose  and  fall  out,  gangrene  of  the  gums, 
lips  and  throat,  and  necrosis  of  part  or  even  of  the  whole  jaw  may  follow. 
The  milder  forms  of  stomatitis  and  salivation  are  observed  in  a  large 
])ro])()rtion  of  cases  of  syi)hilis  treated  with  mercury,  according  to  some 
autliors  in  ;^)0  ])er  cent,  or  more.  It  may  be  avoided,  to  some  extent 
at  least,  by  scrnj)ulous  cleanliness  of  the  mouth  and  teeth,  by  the  filling 
of  carious  teeth,  and  by  using  a  2-4  per  cent,  solution  of  chlorate  of 
])otash  as  a  mouth  wash. 

The  .stomach  and  intestine  also  sull'er  in  chronic  mercury  poisoning. 
The  ])atient  often  c()m])lains  of  loss  of  a])])etite,  and  occasionally  of  a 
feeling  of  weight  and  discomfort  in  the  stomach,  nausea  and  ^•()nliting, 
general  weakness  and  loss  of  flesh.  Colic  and  diarrhoea  are  frequently 
ol)served,  or  diarrhoea  and  constipation  may  alternate.  These  symp- 
toms are  naturally  more  liable  to  occur  from  the  administration  of 


MERCURY  625 

mercury  by  the  inoutli  tluin  l)y  other  chauiiels,  as  here  the  action  after 
absorption  is  reinforced  by  the  (Urect  local  eiVects.  Some  jV'cc/-  is  some- 
times noted,  but  this  is  secondary  to  the  alt'ection  of  the  mouth,  bowel 
or  skin,  and  is  not  directly  attril)utable  to  the  mercury. 

Occasionally  skin  erujAions  are  seen  when  mercury  is  given  by  the 
mouth,  but  much  more  frequently  when  it  is  applied  to  the  skin.  In 
the  latter  case  they  are  not  limited  to  the  point  of  aiJ])licati()n,  although 
they  often  begin  from  it  and  spread  over  a  large  surface  of  the  body. 
They  vary  greatly  in  form,  consisting  of  small  reddish  spots,  large  red 
erythematous  surfaces,  urticaria,  or  eczema,  each  of  these  occurring 
alone  or  in  succession,  and  being  usually  followed  by  desquamation. 
The  eruption  generally  lasts  only  1-3  weeks,  but  in  some  cases  has  not 
entirely  disappeared  until  three  months  after  its  appearance,  and  in 
others  has  returned  repeatedly  afterward.  It  is  said  to  have  been 
induced  occasionally  by  a  single  dose  of  calomel. 

The  urine  is  often  somewhat  increased,  but  may  be  decreased  after- 
ward, and  it  not  infrequently  contains  albumin,  although  the  propor- 
tion of  cases  in  which  this  occurs  is  much  disputed,  and  the  amount 
in  the  urine  is  generally  very  small.  Glycosuria  is  much  rarer  in  man, 
but  has  been  frequently  observed  in  rabbits  after  prolonged  treatment 
with  mercury. 

It  is  still  a  matter  of  doubt  how  far  the  sexual  organs  are  involved 
in  mercury  poisoning.  According  to  some  authorities  disturbances  of 
the  menstruation  and  even  complete  amenorrhoea  have  been  observed, 
and  abortion  is  also  stated  to  have  been  caused  by  it. 

A  general  condition  of  cachexia  may  be  induced  by  these  disorders, 
and  is  marked  by  pallor,  anfemia,  emaciation,  weakness  and  restle'Ss- 
ness,  with  a  tendency  to  fainting  and  disturbed  sleep.  The  pulse  is 
small,  weak  and  quick,  and  the  patient  often  complains  of  breath- 
lessness. 

Affections  of  the  central  nervous  system  are  rarely  induced  now  by  the 
abuse  of  mercury  in  therapeutics,  but  still  occur  in  the  case  of  workers 
in  mercury  mines,  in  mirror,  barometer,  thermometer,  and  other 
manufactories,  in  which  mercury  is  used  and  its  fumes  are  inhaled  by 
the  workmen  for  prolonged  periods.  One  of  these  affections  is  the 
mercurial  erethism,  a  condition  of  abnormal  irritability,  timidity  or 
shyness,  accompanied  by  great  muscular  weakness,  and  sometimes 
developing  into  sleeplessness,  delirium  and  transitory  hallucinations. 
Another  well-known  form  is  the  mercurial  tremor,  which  affects  the 
hands  and  arms  first,  later  the  legs,  and  sometimes  extends  over  all 
the  muscles  of  the  body.  Shooting  pains  along  the  nerves  or  in  the 
joints  are  sometimes  complained  of,  circumscribed  areas  of  partial 
anesthesia,  amblyopia,  anosmia  or  deafness  have  been  described,  and 
in  some  cases  localized  paralysis  of  the  muscles  of  the  arm  or  leg  has 
been  induced. 

The  symptoms  of  mercurial  poisoning,  both  acute  and  chronic,  in 
animals,  resemble  those  in  man  so  closely  that  it  is  unnecessary  to 
describe  them  further. 
40 


620  THE  HEAVY  METALS 

Action. — Lower  Forms  of  Life. — Mercury  is  (Instructive  to  living 
matter  wlierever  it  comes  in  contact  with  it  in  sufficient  concentration. 
This  poisonous  action  is  naturally  much  more  e\ident  when  soluble 
l^rejiarations  are  used  than  when  the  oxides  or  calomel  are  in  question. 
Thus  corrosive  sublimate  in  a  solution  of  one  part  in  50,000  destroys 
infusoria  in  some  20  minutes,  and  even  one  part  in  one  million  kills 
alga^  in  the  course  of  a  few  days.  The  effects  of  mercury  in  syphilis 
arise  from  its  affecting  the  specific  organism  in  a  similar  way,  for  mer- 
cury in  a  dilution  of  one  in  200,000  destroys  spirochjetes  in  the  test- 
tube.  The  exact  amoimt  of  mercury  present  in  an  active  form  in  the 
tissues  cannot  be  estimated,  but  it  ])robably  is  effective  in  still  greater 
dilution  in  cases  of  s\T3hilis.  Here,  as  in  the  case  of  other  specifics 
(quinine,  arsenic,  antimony,  etc.),  mercury  seems  to  have  a  stronger 
affinity  for  the  parasite  than  for  the  tissues  of  the  host,  and  even  than 
for  nearly  related  organisms;  for  mercury  has  little  effect  in  malaria 
or  trypanosomiasis,  that  is,  it  does  not  injure  the  organisms  of  these 
diseases  in  the  same  degree  as  it  does  that  of  sypliilis.  The  bacteria 
are  some\Ahat  more  resistant  than  these  forms,  but  corrosive  sublimate 
is  said  to  delay  the  development  of  some  of  these  in  a  solution  of  one 
part  in  one  million,  and  the  anthrax  bacillus  fails  to  grow  in  blood  which 
contains  one  part  in  8,000.  k  solution  of  one  part  in  one  thousand  is 
generally  regarded  as  capable  of  disinfecting  fluids  completely  in  the 
course  of  a  few  hours,  but  there  is  no  question  that  the  germicidal 
power  of  corrosive  sublimate  has  been  much  overestimated.  Thus 
Geppert  foimd  that  the  spores  of  anthrax  could  be  exi)osed  to  the 
action  of  a  1  per  cent,  solution  for  many  hours  and  still  develop  as  soon 
as  the  mercury  was  entirely  removed.  There  is  no  doubt,  however, 
that  corrosive  sublimate  and  the  other  soluble  salts  of  mercury  are 
among  the  most  powerful  antiseptics  at  present  available.  The  insoluble 
preparations  are  less  poisonous,  owing  to  the  difficulty  in  bringing  them 
into  intimate  contact  with  the  microbes. 

In  the  Higher  Animals  and  in  Man  the  same  destructive  effects  are 
induced  l)y  the  mercury  prei)arations.  The  corrosion  of  the  mouth, 
throat  and  stomach  when  the  perchloride  is  swallowed,  has  already 
been  mentioned.  When  it  is  applied  to  the  other  nnicous  membranes, 
similar  effects  are  obtained,  and  when  it  is  injected  hypodermically, 
even  in  dilute  solution,  it  induces  intense  pain,  swelling  and  inflam- 
mation, which  is  rarely  followed  by  sui)])uration,  but  which  may  result 
in  the  formation  of  cicatrices.  Stronger  solutions  injected  into  animals 
often  cause  the  formation  of  cheesy  abscesses,  and  even  dry  necrosis 
of  the  skin  and  underlying  tissue.  The  hypodermic  or  intramuscular 
injection  of  insoluble  ])rc])arations  is  more  liable  to  cause  abscess  forma- 
tion, because  the  mercury  is  slowly  absorbed  and  has  therefore  more 
time  to  induce  its  irritant  effects. 

When  solutions  of  corrosive  sublinuite  arc  applied  to  the  skin,  they 
cause  a  feeling  of  numbness  very  often ;  but  when  very  strong  solutions 
come  in  contact  with  tender  parts  of  the  skin,  and  in  i^articular.  when 
the  salt  itself  is  allowed  to  lie  in  contact  with  it  for  any  length  of  time, 


MERCURY  627 

cleej)  corrosion,  necrosis,  and  sloughing-  may  follow.  Even  the  insoluble 
l)reparations  are  liable  to  set  up  irritation  when  they  are  rubbed  into 
the  skin,  especially  if  there  is  any  preexisting  tendency  to  cutaneous 
eruption. 

After  absorption,  mercury  acts  more  especially  on  the  alimentary 
tract  and  on  the  kidneys,  although  other  organs  are  not  exempt  from 
its  effects. 

The  Salivation  and  Stomatitis,  which  are  so  frequently  seen  under 
mercurial  medication,  are  obviously  not  due  to  the  local  action  of  the 
drug  on  its  way  to  the  stomach,  for  they  occur  equally  readily  when  it 
is  applied  by  hypodermic  injection  or  by  inunction.  It  is  still  a  matter 
of  doubt  whether  the  salivation  arises  from  the  direct  action  of  the 
mercury  on  the  secretory  apparatus,  or  reflexly  from  the  irritation  of 
the  mouth,  though  it  often  precedes  any  obvious  lesion.  The  saliva 
is  sometimes  excreted  in  enormous  amounts,  many  litres  of  it  being 
poured  out  in  the  course  of  twenty-four  hours.  It  contains  mercury, 
and  has  therefore  a  metallic  taste,  and  tends  to  irritate  the  lips  and 
skin  where  it  comes  in  contact  with  them.  In  extreme  cases  it  leads 
to  sleeplessness  from  its  accumulating  in  the  back  of  the  throat  and 
awakening  the  patient  with  a  feeling  of  suffocation.  The  stomatitis 
is  due  to  the  excretion  of  mercury  by  the  glands  of  the  mouth  and 
throat.  The  irritation  caused  by  the  metal  leads  to  excoriations,  and 
these  to  the  formation  of  ulcers,  particularly  where  microbes  are  present 
in  large  numbers,  as  around  carious  teeth.  The  necrosis  of  the  jaws 
arises  from  these  ulcers  penetrating  to  the  bone  and  setting  up  periostitis, 
for  mercury  in  itself  has  no  specific  action  on  the  bone  such  as  has  been 
mentioned  under  phosphorus. 

Mercury  has  less  direct  effect  on  the  Stomach,  though  congestion 
and  even  small  haemorrhages  in  cases  of  poisoning  indicate  that  it  is 
not  entirely  immune;  the  loss  of  appetite  and  malnutrition  in  chronic 
})oisoning  are  ascribed  to  the  presence  of  mercury  in  the  saliva  rather 
than  to  its  affecting  the  gastric  functions  directly.  In  the  Intestine, 
on  the  other  hand,  mercury  is  apparently  excreted  in  large  amount,  and 
induces  very  distinct  lesions.  The  parts  affected  are  the  csecum  and 
colon,  while  the  small  intestine  very  often  escapes  almost  entirely. 
The  action  of  mercury  is  evidenced  by  hypersemia,  redness  and  swelling 
of  the  mucous  membrane,  which  later  develop  into  necrotic  surfaces 
and  ulcers  along  the  folds;  these  lend  it  an  appearance  almost  indis- 
tinguishable from  that  of  chronic  dysentery  and  may  eventually  end 
in  perforation.  The  symptoms  from  the  intestine  are  in  accordance 
with  the  lesions,  consisting  in  constant  purging  with  very  fluid,  some- 
times rice-water,  stools,  intense  pain  and  tenesmus,  blood  and  fragments 
of  mucous  membrane  in  the  faeces. 

Small  doses  of  mercurials  given  by  the  mouth  act  as  Purges,  causing 
soft  stools  generally  without  pain  or  straining.  The  insoluble  prepara- 
tions— calomel,  blue  pill  and  gray  powder — are  used  for  this  purpose, 
as  they  are  not  dissohed  in  the  stomach  and  are  therefore  devoid  of 
action  there,  while  in  the  intestine  their  longer  sojourn  and  si)ecial 


628  THE  HEAVY  METALS 

affinity  for  tlie  opitlieliTiin  leads  to  tlieir  irritant  action  hoing  developed. 
A  small  proportion  of  these  insoluble  preparations  is  absorbed  from 
the  intestine,  but  the  great  mass  is  thrown  out  unchanged  in  the  stools, 
and  thus  Aery  large  doses  of  calomel  sometimes  induce  no  serious 
sym])toms.  The  stools  after  mercury  are  often  of  a  gray-green  color 
and  this  has  been  attributed  to  the  putrefactive  processes  in  the  bowel 
being  lessened  so  that  the  bile  pigment  retains  its  ordinary  tint.  But 
mercury  acts  when  no  bile  reaches  the  intestine  and  the  stools  are  of 
the  same  greenish  color,  so  that  it  seems  likely  that  this  arises  from 
the  presence  of  some  mercury  compoimd,  probably  some  mixture  of 
sulphides. 

The  mercurial  purges,  and  in  particular  calomel,  have  often  been 
credited  with  increasing  the  secretion  of  the  Bile,  but  this  has  been 
shown  to  be  incorrect,  for  Stadelmann  (in  animals)  and  PfafT  (in  man) 
found  that  they  had  no  effect  on  the  secretion  escaping  from  a  biliary 
fistula.  There  is,  in  fact,  no  sufficient  experimental  or  clinical  evidence 
that  the  liver  is  in  any  way  affected  directly  by  mercury.  The  "  bilious- 
ness" which  is  so  often  relieved  by  calomel  or  blue  pill,  is  due,  not  to 
the  liver,  but  to  disorder  of  the  alimentary  tract. 

]\Iercury  has  no  such  po^^•erfld  effect  on  the  Unorganized  ferments  of 
digestion  as  it  has  upon  the  microbes,  for  though  large  amounts  of  the 
soluble  preparations  precipitate  the  pepsin  in  artificial  digestion  ex- 
periments, smaller  quantities  have  little  effect.  Calomel  has  no  action 
on  the  digesti\'e  ferments,  but  may  retard  the  putrefaction  in  the 
intestine,  and  thus  limit  the  decomposition  of  the  food.  Its  antiseptic 
action  is  aided  by  the  increased  peristalsis  which  follows  its  use,  and 
which  remo\  es  the  decomposing  mass  from  the  canal. 

Another  organ  which  is  powerfidly  affected  by  mercury  is  the  Kidney. 
A  moderate  dose  of  calomel  induces  marked  diuresis,  particularly  in 
cases  in  which  there  is  a  large  accumulation  of  fluid  in  the  body,  as  in 
dropsy  from  heart  disease.  When  jiurging  follows  the  administration 
of  the  mercurial,  less  diuretic  effect  is  observed.  In  normal  individuals 
and  in  animals  the  diuretic  action  is  generally  much  weaker,  although 
some  recent  work  has  shown  that  it  can  be  elicited  easily  in  rabbits 
(Cohnstein).  The  increased  secretion  of  urine  induced  by  calomel  and 
by  other  mercurials  is  most  probably  to  be  ascribed  to  a  direct  action 
on  the  renal  cells. 

In  acute  mercurial  poisoning,  wlien  death  does  not  follow  in  the 
course  of  a  few  hours,  anuria  is  often  obser\'ed  from  inflammation  and 
necrosis  of  the  epithelium  of  the  tubules.  The  whole  organ  is  congested 
and  the  glomeruli  are  in  a  state  of  acute  inflanunation,  but  the  necrosed 
tubules  are  the  most  ])roniinent  feature.  Very  generally  in  the  rabbit, 
less  often  in  the  dog  and  in  man,  these  are  fllled  with  a  dejwsit  of  phos- 
phate of  calcium,  which  is  thrown  out  in  the  necrosed  cells,  and  as  these 
break  up,  passes  into  the  tubules.  It  may  be  remarked  in  passing  that 
several  other  ])oisons,  such  as  bismuth,  and  aloin,  occasionally  iiuhue 
this  de])osit  of  lime  in  the  kidncNs. 

This  renal  necrosis  occurs  chielly  in  corrosi\e  sublimate  poisoning. 


MERCURY  629 

as  the  more  slowly  absorbed,  insoluble  preparations  apparently  do  not 
often  accumulate  in  sufficient  quantity  in  the  blood  to  induce  such 
severe  effects.  At  the  same  time,  albumin  or  casts  are  very  often 
observed  in  the  urine  from  the  treatment  of  syphilitic  patients  with 
mercury  in  any  form,  although  it  is  stated  that  this  is  less  liable  to  occur 
when  soluble  preparations  are  injected  hypodermically  than  after  in- 
unction or  the  use  of  insoluble  salts  subcutaneously.  The  more  marked 
the  action  on  the  intestine,  the  less  destruction  of  the  kidney  is  observed 
in  cases  of  severe  poisoning. 

The  lime  deposited  in  the  kidney  has  suggested  the  idea  that  mercury  causes 
the  absorption  of  the  calcium  in  the  Bones  through  a  specific  action  on  them, 
but  the  lime  deposited  in  the  kidney  is  drawn  from  that  normally  circulating 
in  the  blood;  in  necrosed  tissue  from  other  causes  lime  is  very  often  deposited, 
although  not  so  rapidly  as  in  mercury  poisoning.  Large  doses  given  repeatedly 
lead  to  an  increase  in  the  size  and  number  of  the  vessels  of  the  bone-marrow, 
and  the  fat  cells  atrophy  rapidly;  later  gelatinous  degeneration  follows  and  the 
cellular  elements  of  the  marrow  disappear. 

Mercury  seems  to  have  comparatively  Uttle  direct  action  on  the  Circulation 
in  cases  of  poisoning,  and  most  of  the  changes  in  the  pulse  are  to  be  ascribed 
rather  to  the  shock  and  collapse,  or  in  chroaic  poisoning  to  the  cachexia  and 
malnutrition,  than  to  any  direct  effects  on  the  heart  and  vessels;  in  some  cases 
of  acute  poisoning,  however,  patches  of  fatty  degeneration  have  been  found  in 
the  heart.  In  the  frog  large  doses  of  soluble  salts  slow  and  weaken  the  heart, 
and  mercury  salts  injected  into  the  bloodvessels  of  mammals  have  been  found 
to  cause  a  sudden  descent  of  the  blood-pressure  and  paralysis  of  the  heart. 
Subcutaneously  injected  uito  animals,  the  soluble  salts  reduce  the  blood- 
pressure  more  gradually,  but  at  the  end  a  very  sudden  descent  to  zero  occurs. 
The  action  is  in  part  on  the  heart  muscle,  in  part  on  the  peripheral  vessels. 

The  Respiration  is  also  only  affected  indirectly.  In  chronic  mercury  poisoning 
marked  breathlessness  is  sometimes  observed  and  has  been  ascribed  by  Kuss- 
maul  to  the  general  muscular  weakness. 

The  action  of  mercury  on  the  Nervous  System  is  very  obscure.  In 
acute  poisoning  the  intellect  often  remains  clear  to  the  end,  and  no 
symptoms  pointing  to  any  direct  affection  of  the  central  nervous 
system  are  observed.  In  chronic  poisoning,  however,  the  higher  centres 
are  undoubtedly  involved  in  the  effects,  as  is  shown  by  the  erethism 
and  occasional  halluchiations.  The  tremor  is  also  of  cerebral  origin 
probably,  though  this  is  not  yet  certain,  and  the  general  muscidar 
weakness  is  not  due  to  the  peripheral  muscles  and  nerves  being  affected, 
but  to  the  alterations  in  the  centres.  The  paralysis  sometimes  observed 
in  the  arms  or  legs  in  workers  in  mercury,  and  the  areas  of  partial 
anaesthesia  and  the  pains  in  joints  probably  arise  from  perijiheral 
neuritis.  In  some  cases,  especially  where  the  tremor  is  marked,  the 
reflex  excitability  of  the  spinal  cord  has  been  found  to  be  exaggerated 
but  it  is  generally  unaffected.  The  muscles  do  not  seem  to  be  acted 
on  directly  in  either  acute  or  chronic  poisoning  in  man,  and  even  when 
paralysis  is  developed,  they  maintain  their  irritability  and  do  not 
atrophy. 

A  good  deal  of  interest  has  been  manifested  in  the  question  whether 
mercury  affects  the  Nutrition  in  any  way  except  through  its  action  on 


630  THE  HEAVY  METALS 

the  alimentary  canal.  It  is  stated  Ihat  the  protein  metabolism  is  acceler- 
ated as  is  shown  by  an  increase  in  the  total  nitro<^en,  nrea  and  nric  acid 
in  the  nrine  after  small  doses,  but  the  subject  is  a  very  difficult  one 
to  in\esti^ate,  for  when  any  save  the  smallest  doses  are  gi\en,  the 
kidney  and  bowel  are  involved  in  the  efl'ects,  and  the  prolonged  use  of 
mercury  is  restricted  to  experiments  on  animals  and  on  syjjhilitics. 
1'here  seems,  however,  good  reason  to  believe  that  very  small  doses 
of  mercury  given  for  some  time  increase  the  nutrition  and  weight  of 
animals.  The  cachexia  of  chronic  poisoning  may  be  due  in  part  to  a 
sjjecific  action  on  the  metabolism,  but  it  is  impossible  to  determine 
this  point,  because  the  alterations  in  the  alimentary  tract  are  in  them- 
selves sufficient  to  cause  such  symptoms. 

Changes  in  the  Blood  Corpuscles  have  been  observed  under  mercurial 
treatment  in  a  number  of  instances,  but  there  is  as  yet  no  general 
agreement  as  to  wherein  these  consist,  and  it  seems  not  unlikely  that 
the  blood  reaction  in  health  is  different  from  that  in  sy])hilis  and  that 
it  may  vary  in  the  successive  stages  of  the  disease.  In  health  the  red 
corpuscles  and  the  haemoglobin  are  said  to  be  augmented  at  first  but 
afterward  diminished,  while  in  syphilis  a  sharj)  fall  in  the  amount 
of  luemoglobin  is  succeeded  by  an  increase  to  beyond  that  ])resent 
})efore  the  treatment.  Ku])erwasser  states  that  in  healthy  ])ersons 
mercury  increases  the  number  of  newly  formed  leucocytes  but  that 
this  is  more  than  counterbalanced  by  the  fall  in  the  older  cells;  in 
syphilis  he  foimd  fewer  recently  formed  leucocytes  and  more  mature 
ones  after  mercury. 

Mercury  has  no  effect  on  the  Temperature  in  itself,  but  when  stoma- 
titis or  skin  eruptions  are  developed,  some  fever  generally  accompanies 
them,  while  in  collapse  the  temperature  may  fall  several  degrees  below 
the  normal. 

Distribution. — After  its  prolonged  use  mercury  is  found  in  almost 
every  organ  of  the  body,  but  larger  quantities  are  found  in  the  kidney, 
intestinal  wall  and  liver  than  elsewhere;  considerable  amounts  are 
often  deposited  in  the  liver.  In  cases  of  acute  poisoning  through  ab- 
s()r])tion  from  the  subcutaneous  tissue  or  from  woimded  surfaces,  the 
distribution  is  the  same.  The  statement  that  mercury  is  stored  uj)  in 
large  quantities  in  the  bones  has  not  been  confirmed  by  the  more  recent 
investigators,  but  traces  are  found  here,  as  in  the  muscles,  brain,  lungs, 
intestine,  and  spleen. 

]\Iercury  is  Eliminated  by  almost  all  the  excretory  organs,  but  most 
largely  by  the  intestine  and  kidney.  It  has  been  found  in  small  (pianti- 
ties  in  the  perspiration,  milk,  saliva,  sweat,  gastric  juice  and  bile, 
and  has  been  shown  to  pass  to  the  foetus  in  utero  through  the  ])lacental 
circulation.  The  excretion  in  the  urine  begins  within  an  hour  when 
mercury  is  injected  intravenously,  but  more  slowly  by  the  ordinary 
methods  of  administration;  for  examj)le,  after  inunction,  none  may  be 
found  for  twenty-four  hours.  The  quantity  eliminated  daily  rises 
slowly  during  tlie  treatment  and  then  falls  gradually.  The  excretion 
is  ver\'  slow  and   varies  according  to  tlu'  method  of  administration; 


MERCURY  G31 

there  is  no  question  however,  that  after  the  usual  methods  of  adminis- 
tration in  syphihs  mercury  is  found  in  the  urine  for  months  and  in 
some  cases  for  years  after  the  last  dose.  No  accurate  estimation  of 
the  mercury  excreted  in  the  faeces  has  been  made,  but  it  is  believed 
that  less  is  excreted  here  than  in  the  urine  at  first,  but  that  later  the 
greater  part  may  pass  out  by  the  intestine.  The  administration  of 
potassium  iodide  does  not  accelerate  the  elimination  of  mercury.  In 
the  urine  the  mercury  probably  exists  for  the  most  part  in  the  form 
of  a  salt,  although  some  of  it  may  be  in  organic  combination. 

Mercury  forms  very  poisonous  compounds  with  methyl  and  ethyl,  which  are 
apparently  slowly  decomposed  in  the  organism  to  ordinary  forms,  and  which 
have  given  rise  to  fatal  poisoning  in  two  cases,  the  symptoms  making  tlieir 
appearance  only  long  after  the  ingestion.' 

Therapeutic  Uses. — The  chief  purpose  for  which  mercury  is  used 
internally  is  the  treatment  of  Syphilis.  Its  curative  effects  in  this 
disease  are  due  to  its  specific  destructive  action  on  the  spirochsete 
pallidum,  the  organism  of  syphilis.  Long  a  subject  of  discussion, 
its  usefulness  in  this  infection  is  now  acknowledged  by  all  who  have 
studied  the  subject.  It  is  true  that  mild  cases  sometimes  recover  with- 
out the  use  of  mercury,  but  even  these  run  a  shorter  course  if  mercury 
is  administered.  And  in  many  others,  in  which  the  symptoms  show 
no  signs  of  abating  under  hygienic  measures,  mercury  causes  a  rapid 
and  permanent  improvement.  A  certain  mmiber  of  relapses  undoubt- 
edly occur  after  the  mercurial  treatment  has  been  left  off,  but  it  seems 
probable  that  many  of  these  would  not  have  had  even  temporary 
relief  without  mercury.  In  a  certain  proportion  of  malignant  forms 
mercury  is  unable  to  arrest  the  progress  of  the  disease.  And  when  the 
organism  has  invaded  the  central  nervous  system,  mercury  does  not 
seem  to  be  able  to  reach  it,  for  no  improvement  is  obtained  from  its 
use  in  tabes  or  in  the  general  paralysis  of  the  insane. 

The  effects  of  mercury  in  syphilis  present  many  analogies  to  that  of 
arsenic  and  antimony  in  trypanosomiasis;  in  each  a  protozoal  parasite 
in  the  tissues  is  in  some  cases  destroyed  by  the  specific  remedy,  and 
this  is  fortunately  often  complete  in  sAi^hilis;  but  in  other  cases  a 
relapse  occurs  from  some  of  the  organisms  surviving  the  first  treatment. 
In  the  case  of  the  trypanosomes  these  survivors  are  more  resistant  to 
the  specific  than  the  original  infection,  but  this  has  not  been  shown 
to  be  the  case,  at  any  rate  in  the  same  degree,  in  syphilis. 

The  recent  introduction  of  the  organic  arsenic  compounds  has  not 
led  to  the  mercurial  treatment  being  abandoned,  for  it  is  found  necessary 
to  combine  the  action  of  both  parasiticides  to  obtain  the  best  results 
in  the  treatment  of  s\T3hilis.  The  injection  of  salvarsan  ought  to  be 
followed  by  a  vigorous  use  of  mercury  until  the  specific  Wassermann 
reaction  disappears  and  remains  absent. 

The  study  of  the  arsenic  treatment  seems  to  have  finally  determined 
a  long  debated  question,  whether  mercury  should  be  exhibited  in  the 

'  Hepp.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxiii,  p.  91. 


632  THE  HEAVY   METALS 

l)riiiiary  stage  of  syphilis.  The  danger  of  a  widespread  infection,  possibly 
involving  the  central  nervous  system,  is  now  recognized  to  be  so  great 
that  no  delay  is  permissible;  vigorous  treatment  with  salvarsan  and 
mercury  should  be  instituted  as  soon  as  the  disease  is  diagnosed  and 
should  be  continued  as  long  as  there  is  any  risk  of  a  relapse.  The 
treatment  with  mercury  is  not  so  heroic  as  a  century  ago,  and  all  are 
agreed  that  it  ought  not  to  be  allowed  to  induce  any  but  the  earliest 
sym])toms  of  chronic  poisoning.  In  tertiary  sy])hilis  mercury  is  generally 
associated  with  the  iodides,  as  it  is  found  that  the  resolution  of  the 
new-grown  tissue  by  the  latter  facilitates  the  destruction  of  the  spiro- 
cha'te  by  the  mercury.  In  animals  mercury  in  large  doses  has  been 
found  to  i)revent  infection  with  syphilis. 

Mercury  has  been  used  in  syphilis  in  a  large  number  of  forms,  and 
of  late  years  many  new  preparations  and  new  methods  of  administra- 
tion have  been  proposed.  Mercury  cures  syphilis  by  destroying  the 
organism,  and  this  object  is  to  be  attained  by  introducing  enough  of 
the  metal  to  act  on  the  spirocha?te  without  inducing  symptoms  from 
its  action  on  the  tissues.  The  estimation  of  the  metal  absorbed  by 
the  different  forms  of  treatment  is  thus  of  much  interest,  and  a  fairly 
accurate  idea  of  the  amount  absorbed  appears  to  be  given  by  that 
excreted.  The  best  clinical  results  appear  to  follow  from  a  rapid  al)- 
sorption  and  prolonged  excretion,  as,  if  the  stay  of  the  mercury  in 
the  tissues  is  short,  relapses  are  liable  to  occur.  Formerly  mercury 
was  given  by  the  month  or  by  inunctioii,  and  apart  from  the  special 
clinics  and  the  syphilologists,  the  internal  treatment  is  still  the  most 
p()l)ular  one.  The  preparations  generally  used  for  internal  adminis- 
tration are  corrosive  sublimate,  calomel,  or  the  metallic  ])rei)arations 
— blue  pill  and  gray  powder — the  last  being  used  most  widely  in  Eng- 
land. Calomel  and  the  metallic  preparations  are,  however,  very  liable 
to  induce  diarrha'a,  from  their  being  insoluble  and  thus  passuig  into 
tlie  intestine  before  being  absorbed,  and  opium  is  therefore  often 
prescrilied  along  with  them.  Calomel  is  also  credited  with  causing 
salivation  and  stomatitis  more  readily  than  the  other  preparations, 
perhaps  l^ecause  it  is  more  difficult  to  gauge  how  much  of  it  is  absorbed 
than  in  the  case  of  the  soluble  perchloride.  Large  amounts  of  mercury 
have  been  shown  to  be  absorbed,  when  calomel  and  other  salts  are  taken, 
but  the  concentration  in  the  blood  ai)i)ears  to  vary  more  irregularly 
from  day  to  day  than  when  other  methods  are  employed.  And  mercury 
administered  by  the  mouth  is  in  all  cases  more  liable  to  derange  the 
digestion  than  when  administered  by  other  channels,  and  on  the  whole 
is  less  certain  and  less  satisfactory  in  its  results. 

Invndiun  was  introduced  to  avoid  the  disturbance  of  the  stomach 
and  intestine  caused  by  the  local  action  of  the  mercury,  while  that  due 
to  its  excretion  along  the  alimentary  tract  remained  unchanged.  Mer- 
cury ointment  is  rubbed  into  the  skin  and  is  absorbed  ui  ])art  from  the 
"ducts  of  the  glands  and  ui  i)art  by  the  lungs  as  va])or.  'J'he  abs()r])ti()n 
is  .slower  than  by  internal  administration,  but  is  more  regnlar  and 
lasts  longer  and  there  is  less  disturbance  of  digestion.     Tlu>  objection 


MERCURY  633 

to  the  method  is  that  it  is  inconvenient  and  uncleanly,  and  that  it  is 
even  less  i)()ssible  to  estunate  the  amount  of  mercury  actually  al)S()rbed 
than  when  it  is  given  by  the  mouth.  Instead  of  mercury  ointment 
being  rubbed  into  the  skin,  one  of  the  plasters,  or  lint  containing 
mercurial  ointment  (Weylander) ,  may  be  applied  to  it,  permitting 
of  the  continuous  absorption  of  small  quantities  by  the  skin  and  by 
inhalation  of  the  vapor.  Or  a  mild  effect  may  be  induced  by  mercury 
in  a  state  of  fine  division  being  carried  in  a  bag  in  the  clothing. 

In  1867,  Lewin  introduced  the  hypodermic  or  intramuscular  injection. 
of  a  dilute  solution  of  corrosive  sublimate,  and  this  has  been  very 
widely  practised  of  late  years,  and  with  great  success.  The  advantages 
of  the  method  are  the  avoidance  of  digestive  disturbance,  which  is 
shared  by  the  inunction  method,  its  cleanliness,  the  more  accurate 
estimation  of  the  amount  of  mercury  actually  administered,  and  the 
greater  rapidity  of  action.  The  absorption  is  very  rapid,  mercury 
appearing  in  the  urine  in  the  course  of  an  hour,  but  the  maximum 
is  soon  reached  and  much  of  the  metal  is  eliminated  in  two  or  three 
days.  Its  chief  disadvantage  is  the  pain  caused  by  the  injection,  which 
has  to  be  repeated  daily;  some  inflammation  and  swelling  follow 
immediately,  but  no  suppuration,  when  ordinary  care  is  taken;  but  the 
pain  is  very  intense  and  persistent  and  many  patients  refuse  to  continue 
the  treatment.  Salivation  is  said  to  follow  this  method  more  seldom 
than  any  other,  and  relief  from  the  secondary  syphilitic  symptoms 
is  gained  sooner.  Lewin  continues  to  use  the  perchloride  solution 
and  prefers  it  to  any  of  the  modifications;  sodium  chloride  or  urea 
is  often  added  to  prevent  the  precipitation  of  proteins  and  the  con- 
sequent local  irritation.  Others  have  advocated  mixtures  with  peptone 
or  albumin,  or  salts  of  mercury  with  an  amino-acid,  such  as  glycin, 
formamide,  or  succinimide.  These  methods  are  said  to  lessen  the  pain 
of  hypodermic  injection,  but  do  not  remove  it  entirely,  probably  because 
the  various  compounds  undergo  some  dissociation  in  the  tissues,  and 
the  free  mercury  ion  causes  the  same  irritation  as  if  the  perchloride  had 
been  injected. 

Instead  of  the  soluble  preparations  of  mercury,  which  necessitate 
the  painful  injections  being  repeated  daily,  insoluble  salts  have  been 
injected  into  the  muscles  with  the  idea  that  these  being  slowly  dis- 
solved and  absorbed  from  the  seat  of  injection,  a  quantity  sufficient 
for  several  days  may  thus  be  given  at  one  time.  The  immediate  pain 
is  less  than  from  perchloride  injections,  but,  as  solution  takes  place, 
and  the  mercury  attacks  the  tissues,  the  part  becomes  extremely  pain- 
ful, swollen,  and  inflamed.  Suppuration  and  even  gangrene  have 
been  developed  in  a  very  considerable  number  of  cases,  and  in  others 
severe  or  fatal  mercury  poisoning  has  been  observed.  The  advantages 
of  the  method  are  that  the  physician  has  not  to  visit  the  patient  every 
day,  and  that  the  injection  need  only"  be  made  once,  or  at  most  twice 
a  week.  On  the  other  hand,  the  local  lesions  are  often  very  severe, 
and  the  amount  of  mercury  absorbed  cannot  be  controlled  in  any  way. 
It  has  the  advantage  over  the  administration  per  os  that  the  digestion 


G34  TflE  HEAVY  METALS 

is  not  so  liable  to  be  disturbed.  In  spite  of  its  drawbacks,  this  method 
has  gained  a  wide  popularity  and  is  considered  more  certain  than  any 
of  the  others  except  the  injection  of  ])er('hloride,  wliich  shares  its  dis- 
adxantajies.  The  amount  of  mercury  in  the  circulation  (as  measured 
by  that  excreted)  is  subject  to  less  variation  than  is  the  case  with  other 
methods  except  inunction,  which  is  much  slower  in  effect.  The  pre- 
parations most  commonly  used  are  calomel  suspended  in  salt  solution 
or  in  licpiid  paraffin,  metallic  mercury  in  very  fine  division  suspended 
in  liquid  i)araffin,  the  salicylates  and  the  thymol-acetate.  The  oxides 
have  also  been  proposed,  and  many  other  preparations  have  received 
a  trial  by  this  method. 

Other  methods  of  introducing  mercury  into  the  tissues  are  more  rareh' 
employed.  The  intravenous  injection  of  the  perchloride  has  been  suggested 
for  the  treatment  of  cases  in  which  there  is  urgent  haste,  but  is  scarcely  to 
be  recommended  in  ordhiary  infections,  as  there  is  danger  of  embolism;  and 
while  the  blood  contains  a  large  quantity  for  a  short  time,  the  concentration 
falls  very  rapidlj^  from  the  metal  being  eliminated. 

Supposituries  of  mercury  have  been  used  to  some  extent  and  are  said  to 
disturb  the  digestion  less  than  the  administration  per  os. 

Mercurj^  fumigations  have  also  been  practised  to  a  limited  extent,  the  vapor 
of  mercury  being  freed  by  heating  calomel  or  the  sulphidfe.  The  patient  sits 
in  a  wooden  tent  up  to  his  neck,  and  the  mercury  deposited  on  the  skin  is 
absorbed.  The  method  is  very  cumbrous  and  the  cjuantity  of  mercurj'  taken 
up  cannot  be  controlled. 

The  Other  Protozoal  Infections  are  not  so  amenable  to  mercurial 
treatment  as  syphilis,  and  it  has  pro\'ed  of  no  value  in  malaria  or  try- 
panosomiasis. Some  spirillar  infections  in  animals  are  said  to  react 
to  mercury  in  the  same  way  as  syphilis,  however. 

Mercury  was  recommended  by  Hamilton  in  the  beginning  of  the  last 
century  in  the  treatment  of  Acute  Febrile  Affections,  and  the  greatest 
abuse  unquestionably  prevailed  in  the  earlier  decades.  Later  its  sphere 
of  usefulness  was  restricted  to  the  treatment  of  inflammation  of  the 
serous  membranes — pleurisy,  meningitis,  pericarditis,  peritonitis — but 
its  usefulness  in  these  conditions  has  ne\er  been  established  and  its 
employment  is  now  more  limited;  in  acute  iritis  it  is  still  used  almost 
universally.  In  these  cases  it  is  always  administered  by  the  mouth  in 
the  form  of  calomel,  blue  pill,  or  gray  powder. 

As  a  Purgative  mercury  is  very  frequently  ])rescril)ed  in  "bilious- 
ness" and  in  ])utrefactive  diarrha^a.  It  acts  partly  from  its  anti- 
septic power,  but  mainly  by  removing  the  putrefying  contents  from 
the  intestine;  calomel,  blue  })ill,  or  gray  powder  is  usually  em])loycd 
with  or  without  the  addition  of  a  vegetable  purge. 

Calomel  has  proved  of  only  doubtful  ^■alue  as  an  intestinal  anti- 
septic in  typhoid  fever,  dysentery,  and  other  similar  conditions. 

Calomel  and  other  mercurials  have  long  been  known  to  be  of  \  aluc 
in  cases  of  Dropsy.  '^Ihe  best  ])r(>]iaration  is  calomel,  given  in  O.'J  C. 
(.S  grs.)  doses  three  times  a  day  or  in  0.1  (i.  (2  grs.)  doses  (i\c  times 
a  day.      It  is  of  great  \alue  in  certain  eases  of  cardiac  dropsy,  but   is 


MERCURY  635 

less  reliable  in  the  accumulations  of  fluid  met  with  in  hepatic  or  renal 
disease,  although  here  too  its  administration  is  sometimes  followed  by 
the  rapid  excretion  of  the  fluid.  It  does  not  seem  to  be  contraindicated 
in  chronic  nephritis,  although  its  action  has  to  be  carefully  controlled. 
It  has  no  effect  in  removing  the  exudations  of  acute  inflammation 
such  as  pleurisy. 

Mercury  is  used  Externally  as  a  Disinfectant  wash  in  surgical  opera- 
tions, chiefly  in  the  form  of  the  perchloride,  but  also  as  the  cyanide 
and  oxycyanide.  It  is  irritant  to  wounds,  however,  and  is  liable  to  be 
absorbed  when  applied  to  large  surfaces,  and  several  cases  of  fatal 
poisoning  have  been  recorded  from  the  use  of  even  the  most  dilute 
solutions  of  corrosive  sublimate  to  wash  out  the  uterus  and  vagina. 
These  preparations,  more  especially  the  perchloride,  have  also  the 
disadvantage  of  attacking  steel  instruments. 

Numerous  ointments  have  been  applied  externally  in  the  treatment 
of  Skin  Diseases,  particularly  those  of  a  parasitic  nature,  such  as  itch, 
and  in  condylomata,  ulcers,  and  skin  diseases  of  syphilitic  origin.  These 
preparations  combine  a  disinfectant  with  a  more  or  less  irritant  action, 
and  unlike  carbolic  acid  and  its  allies,  are  equally  powerful  antiseptics 
in  ointments  and  in  water.  The  least  irritant  of  the  pharmacopoeial 
ointments  is  the  mercury  ointment;  then  the  oleate,  yellow  oxide, 
red  oxide  and  ammoniated  mercury  follow  in  order,  while  citrine  oint- 
ment is  much  more  irritant  and  corrosive.  Other  external  applications 
are  the  plasters  and  the  black  and  yellow  wash.  Ointments  containing 
calomel,  corrosive  sublimate  and  other  preparations  are  sometimes 
prescribed,  or  calomel  may  be  used  as  a  dusting  powder  in  syphilitic 
ulcers.  The  mercury  ointments  are  frequently  applied  to  the  eye, 
the  milder  ones  as  antiseptics  and  slight  irritants,  citrine  ointment  to 
destroy  granulations. 

Mercurial  ointments  are  sometimes  employed  to  promote  the  absorp- 
tion of  subcutaneous  effusions  and  to  reduce  swellings.  They  are  not 
superior  to  other  irritants  for  this  purpose,  however,  and  have  the 
disadvantage  of  permitting  the  absorption  of  a  dangerous  poison. 

The  nitrate  of  mercury  and  its  ointment  (citrine)  are  sometimes 
used  as  caustics  for  application  to  the  os  uteri,  condylomata,  and 
elsewhere. 

IMercury  treatment  is  Contraindicated,  or  requires  special  caution  in 
cases  of  profound  cachexia,  weakness  or  antemia,  unless  these  arise 
from  syphilis.  Where  the  digestion  is  weak,  it  ought  to  be  avoided  if 
possible,  and  in  cases  of  tuberculosis  there  is  always  the  danger  that 
the  disturbance  of  the  digestion  may  accelerate  the  course  of  the  dis- 
ease. In  severe  nephritis  it  is  also  to  be  used  with  caution,  although 
it  is  beneficial  in  some  cases,  and  although  some  authorities  deny  that 
it  is  injurious  even  when  it  has  no  diuretic  action.  In  pregnancy  mer- 
cury is  not  absolutely  contraindicated,  at  any  rate  up  to  the  sixth 
month.  Later  it  is  liable  to  injure  the  patient  by  its  action  on  the 
digestion,  and  in  some  cases  has  induced  abortion;  the  child  may  also 
sufl'er    from    mercurial    poisoning.      Mercurial    ointments    or    dusting 


636  THE  HEAVY   METALS 

powders  ha\e  to  be  used  with  care  when  iodides  are  being  administered 
internally,  as  the  iodide  of  mercury  may  be  formed  and  may  cause 
\  iolent  corrosion.  Thus  in  the  eye,  se\'ere  effects  have  been  induced 
by  the  application  of  calomel  to  the  cornea  while  iodide  of  potassium 
was  being  given. 

In  cases  of  Acute  Corrosive  Poisoning,  the  indications  are  the  e\acua- 
tion  of  the  stomach,  ])referal)ly  l)y  the  stomach  tube.  Tannic  acid, 
or  eggs,  milk  and  other  albuminous  substances  may  l)e  given  to  pre- 
cipitate the  metal  and  protect  the  mucous  membrane.  The  treatment 
of  the  later  symptoms  is  the  same  as  that  of  the  chronic  form. 

In  Chronic  Poisoning  the  salivation  and  stomatitis  are  treated  by  the 
use  of  potassium  chlorate  solution  as  a  mouth  wash,  and  its  free  applica- 
tion during  mercurial  treatment,  along  with  careful  brushing  of  the 
teeth,  is  believed  by  most  physicians  to  hinder  the  onset  of  the  symp- 
toms. Tannic  acid  solution  is  also  recomniended  as  a  mouth  wash. 
The  <liarr]ia'a  may  be  treated  with  o])iimi,  the  other  symptoms  on  general 
principles.  In  any  case  the  drug  ought  to  be  abandoned,  or  the  dose 
much  reduced  as  soon  as  the  salivation  becomes  marked.  Iodide  of 
potassium  and  hot  baths  or  sulphur  baths  are  often  ad\ised  in  chronic 
poisoning  with  tlie  ^•iew  of  accelerating  the  elimination  of  the  metal, 
but  careful  estimations  liave  shown  that  they  have  no  such  effect. 

Preparations. 

IIydrargyri  CHLORmuM  CoRROsivuM  (U.  S.  p.),  Hydrargyri  Perchlo- 
RiDUM  (B.  p.),  CORROSIVE  SUBLIMATE  (HgCl2)  forms  heavv,  colorless  crystals, 
without  odor,  \mi  possessing  an  acrid,  metallic  taste,  soluble  in  Hi  parts  of 
cold  water,  in  2  parts  of  boiling  water,  in  8  parts  of  alcohol  Dose,  3  nig. 
(.',,  gr.);  B.  P.,  .WVgr. 

LiQi:oR  Hydrargyri  Perchloridi  (B.  P.)  (0.1  per  cent.),  ^-1  fl.  dr. 

Corrosive  sublimate  is  one  of  the  most  irritant  preparations  and  is  rapidly 
alisorbed.  It  is  used  internally  in  syphilis  in  1  per  cent,  solution  and  is  also 
injected  intramuscularly  in  0.6  per  cent,  solution,  2  c.c.  (30  mins.)  daily.  This 
solution  is  often  made  up  with  6  per  cent,  of  sodium  chloride  or  urea.  Perchloride 
of  mercury  is  less  liable  to  induce  salivation,  but  disturbs  the  digestion  more  than 
other  preparations  when  given  internally,  while  its  hypodermic  injection  is 
exceedingly  painful.  It  has  induced  fatal  jjoisoning  in  the  dose  of  0.18  G.  (3  grs.), 
taken  by  the  mouth,  but  other  cases  have  recovered  from  nuich  larger  quantities. 
It  is  stated  that  opium  eaters  can  take  enormous  quantities  without  evil  etTects. 

It  is  u.sed  extensively  in  surgery  as  an  antiseptic  solution  (1  in  2,000^4,000), 
to  disinfect  the  hands,  wounds,  etc.,  but  is  irritant  to  delicate  tissues,  such 
as  the  peritoneum,  and  corrodes  steel  instruments.  It  is  also  used  in  the  form 
of  a  soap  and  to  impregnate  bandages,  cotttm-wool,  gauze,  catgut,  and  silk. 
It  preserves  its  antiseptic  action  in  oils  and  ointments.  It  has  been  used  to  a 
limited  extent  in  skin  diseases  in  solution,  in  l)ath.s,  or  in  ointment,  as  a  local 
aj)i)lication  in  dii)litheria,  and  as  an  intestinal  antiseptic  in  putrefactive  diarrluea, 
tyi)h()id  fever  and  cholera. 

Hydrargyri  Iodidum  Rubrum  (U.  8.  P.,  B.  P.),  red  iodide  of  mercury, 
biniodide  of  mercury  (Hglj),  a  scarlet-red  amorphous  powder,  tasteless  and 
odorless,  almost  insoluble  in  water,  but  soluble  in  solution  of  iodide  of  potassium. 
3  mg.  (,'„  gr.);  ]i.  P.,  ,>,-,",,  gr. 

This  preparation  is  very  seldom  prescribed  as  such,  l)ut  is  freciuently  lornied 
by  prescribing  a  mixture  of  corrosive  sublimate  and  jjotassic  ioilide,  when  the 
iodide  of  mercury  is  formed  and  is  kept  in  solution  by  the  excess  of  the  iodide 


MERCURY  637 

of  potassium.  This  i)r(\scriptioii  is  often  iiulicafcd  in  fcrtiarv  syphilis.  The 
yellow  or  green  iodide  of  mercury  (Hgl)  has  also  been  used  in  syphilis,  but  has 
no  advantages  over  calomel. 

Liquor  Arscni  d  Hydrargyri  lodjdi  (U.  S.  P.,  15.  P.),  l^onovan's  solution, 
contains  1  per  cent,  each  of  arsenic  iodide  and  red  mercuric  iodide.  0.1  c.c. 
(U  mins.);  B.  P.,  5-20  mins. 

Ungucnium  Hydrargyri  lodidi  Rubri  (B.  P.),  4  per  cent. 
Hydrargyri  Chloridum  Mite  (U.  S.  P.),  Hydrargyri  Subchloridum 
(B.  P.),  mild  mercurous  chloride,  calomel  (Hg2Cl2),  a  heavy  white  powder, 
without  odor  or  taste,  insoluble  in  water,  alcohol  and  ether.  0.06;3-0.12o  G. 
(1-2  grs.);  B.  P.,  ^-5  grs.,  in  powder  or  tablets,  less  suital)ly  in  pill  form. 
Calomel  is  contained  in  the  compound  cathartic  pill  U.  S.  P.  (p.  107). 
Calomel  is  used  in  syphilis  (dose,  0.05  G.  (1  gr.)  thrice  daily),  but  is  credited 
with  being  more  Habl(rTo~induce  salivation  than  other  preparations,  and  its 
purgative  action  often  has  to  be  counteracted  by  opium.  A  suspension  of  1 
part  calomel  in  20  parts  of  10  per  cent,  salt  solution  or  liquid  paraffin  is  often 
injected  into  the  buttock  in  syphihs;  the  dose  of  calomel  by  this  method  is 
0.05-0.1  G.  (1-H  grs.)  once  a  week.  As  a  purge  and  intestinal  disinfectant 
it  is  of  value  in  bihousness  and  in  the  diarrhoea  of  putrefaction,  less  so  in  diseases 
in  which  the  intestinal  wall  is  the  site  of  infection,  as  in  typhoid  fever  and 
cholera.  Calomel  causes  less  irritation  and  colic  than  most  other  purges, 
and  small  doses  are  followed  by  onlj^  one  evacuation.  It  may  therefore  be 
given  where  preexisting  irritation  of  the  intestine  contraindicates  the  use  of 
most  other  purgatives.  Calomel  is  often  advised  in  hepatic  affections,  but  it 
is  a  ciuestion  whether  it  has  any  effect  here  except  as  a  purge.  It  is  of  great 
value  in  some  forms  of  dropsy,  especially  those  of  cardiac  origin,  in  which  it 
is  administered  in  0.2  G.  (3  gr.)  doses  thrice  a  day  for  2-4  days,  and  is  stopped 
as  soon  as  the  cUuresis  sets  in.  The  treatment  ma}'  be  repeated  if  the  dropsy 
returns. 

Calomel  has  been  used  externally  as  a  dusting  powder  for  sj-philitic  cond}^- 
lomata,  as  a  slight  irritant  to  the  cornea,  and  as  an  ointment  in  pruritus  and 
other  skin  diseases. 

Hydrargyrum  cum  Creta  (U.  S.  P.,  B.  P.),  mercury  vdth  chalk,  gray 
POWDER,  is  formed  by  rubbing  up  metallic  mercurj'-  with  chalk  and  honey 
(U.  S.  P.)  until  the  mercury  is  divided  into  very  fine  globules,  each  encased  in 
chalk.  It  forms  a  light-gray,  somewhat  damp  powder,  without  odor  and  with 
a  sweetish  taste  from  the  hone}'.  The  mercury  (3S  per  cent.  U.  S.  P.,  33  per 
cent.  B.  P.)  remains  in  the  metallic  state,  very  little  oxide  being  formed.  It  is 
insoluble  in  water,  alcohol  and  ether,  and  is  always  prescribed  in  powder  form. 
0.25  G.  (4  gr.);  B.  P.,  1-5  grs. 

IMassa  Hydrargyri  (U.  S.  P.),  mass  of  mercuiy,  blue  mass,  blue  pill, 
is  formed  from  metallic  mercury  by  rubbing  it' with  Mel  Rosse,  gtycerin,  althaea 
and  liciuorice  until  the  globules  are  invisible  under  a  lens  magnifA'ing  ten 
diameters.  The  blue  mass  contains  about  33  per  cent,  of  mercury  almost 
entirely  in  the  metallic  fonn.  It  is  of  the  consistency  of  pills  and  is  alwa3's 
prescribed  in  this  form.     0.25  G.  (4  grs.). 

Pilula  Hydrargyri,  blue  pill,  the  corresponding  B.  P.  preparation,  is 
made  up  with  confection  of  roses  and  liquorice  bj'  rubbing  them  with  metallic 
mercury  until  the  globules  are  no  longer  visible.    4-8  grs. 

These  preparations  are  verj^  largely  used  as  mild  mercurial  ])urgatiA-es, 
the  blue  pill  being  frequentlj'  reinforced  by  the  addition  of  one  of  the  vege- 
table purges.  The  gray  powder  is  especially  adapted  for  children,  and  is  of 
value  in  sunnner  diarrhoea  and  other  similar  conditions.  Blue  pill  is  often 
given  in  cardiac  dropsy  along  with  sciuills  or  digitalis,  but  has  proved  inferior 
to  calomel  as  a  diuretic.  Gray  powder  is  held  by  some  authorities  to  be  the 
best  form  for  the  internal  treatment  of  syphilis,  and  is  given  in  doses  of  0.05  G. 
(1  gr.)  3  to  5  times  a  day;  if  necessary,  opium  may  be  gi\'en  to  prevent  purging. 
The  blue  pill  maj'  also  be  used  in  syphilis  and  is  less  liable  to  purge. 


038  THE  HEAVY   METALS 

Unouentum  IIydrarcyhi  (U.  S.  P.,  B.  P.),  mercurial  ointment,  blue  oint- 
ment, is  formed  by  trituratinj^  metallic  mercury  with  lanl  and  suet  until  the 
globules  arc  invisible  when  maf2;nified  ten  diameters.  The  ointment  contains 
about  50  per  cent,  of  metallic  mercury  U.  8   P.,  30  per  cent.  B.  P. 

I'ltgucntiim  Hydrargyri  Compositum  (B.  P.)  contains  12  per  cent,  of  mercury 
along  with  cam]ihor. 

I'ligucntum  Hydrargyri  Dilidum  (U.  S.  P.)  contains  33  per  cent,  of  mercury. 

The  famous  blue  ointment  is  used  largely  in  manj'  forms  of  skin  disease, 
espcH'ially  in  those  of  syphilitic  origin,  and  was  formerly  the  ordinary  treat- 
ment for  scatjies,  in  which,  however,  it  has  been  supplanted  by  balsam  of  Peru 
and  other  remedies,  though  it  is  still  used  occasionally  to  destroy  pediculi. 
The  most  important  purpose  for  which  blue  ointment  is  api)lied  at  the 
present  time  is  the  treatment  of  syphilis  by  inunction.  For  this  purpose  2-4  (1. 
(5-I  dr.)  is  rubbed  in  daily  in  different  jjarts  of  the  body,  in  order  to  avoid 
the  irritation  induced  by  api)lying  it  repeatedly  to  one  spot.  A  warm  bath 
is  taken  first,  and  the  patient  then  rubs  in  the  ointment  on  the  inside  of  the 
thighs,  next  day  on  the  inside  of  the  arms,  on  the  follo^\dng  days  on  the  forearms, 
legs,  abdomen  and  back,  returning  to  the  thighs  on  the  seventh  day  and  repeating 
the  series.  The  treatment  is  continued  for  a  fortnight  or  three  weeks.  This 
method  has  the  advantage  that  the  digestion  is  less  affected  than  when  the 
drug  is  given  internally,  but  on  the  other  hand,  the  mercury  is  more  slowly 
at)sorl)ed  than  by  other  methods;  and  no  estimate  of  the  quantity  really  taken 
uji  can  be  formed,  as,  although  the  patient  is  directed  to  rub  it  in  until  the  whole 
disappears,  the  instructions  may  be  imperfectly  carried  out.  Salivation  is  not 
so  readily  produced  as  by  the  administration  per  os,  but  when  it  occurs,  it  lasts 
longer  and  may  become  severe.  One  case  of  fatal  poisoning  has  been  recorded 
from  the  application  of  the  ointment,  but  in  this  case  the  skin  appears  to  have 
been  broken.  Skin  rashes  are  more  frequent  from  inunction  than  from  any 
other  method  of  application,  and  finally,  the  method  is  extremely  incon\-enient 
and  dirty.  In  children  the  ointment  is  often  applied  by  spreading  it  on  a  bandage 
which  is  then  applied  around  the  waist.  In  skin  disease  and  in  very  hirsute 
individuals,  the  inunction  treatment  is  impossible. 

Oleum  Cinereum,  or  gray  oil  (not  official),  is  a  suspension  of  inetallic  nier- 
cury  in  liquid  paraffin  or  in  lanolin  and  oil,  and  is  used  in  syphilis  by  intra- 
muscular injection.  It  often  is  made  up  to  contain  20  per  cent,  of  mercury, 
and  the  dose  is  then  2-3  c.c.  once  a  week.  Lambkin's  Cream  is  a  similar  10 
I)er  cent,  suspension  of  mercury  in  lanohn  and  liquid  paraffin. 

Oleatum  Hydrargyri  (U.  S.  P.),  Hydrargyrum  Olcatum  (B.  P.),  oleate  of 
mercury,  has  been  used  for  the  same  i)urposes  as  mercury  ointment,  but  is 
somewhat  more  irritant  and  possesses  no  compensating  virtues. 

Uhguentum  Hydrargyri  Oleati  (B.  P.),  1  part  in  4. 

Emplastrum  Hydrargyri  (U.  S.  P.,  B.  P.),  mercury  plaster,  is  formed  in  the 
same  way  as  the  ointment  by  the  trituration  of  metallic  mercury. 

The  plaster  is  sometimes  applied  to  chancres  and  to  syphilitic  ulcers,  and 
has  l)ccn  used  instead  of  the  ointment  as  a  treatment  of  syphilis. 

IlYDRAiKiYui  OxiDUM  Flavlm  (U.  S.  P.,  B.  P.),  ycllow  mercuric  oxide. 

IIydraugyki  Oxidum  Pubrum  (U.  S.  P.,  B.  P.),  red  mercuric  oxide. 

Unguentum  Hydrargyri  Oxidi  Flavi  (U.  S.  P.,  10  per  cent.,  B.  P.,  2  per 
cent.). 

Unguentum  Hydrargyri  Oxidi  Rubri  (U.  S.  P.,  B.  P.),  10  per  cent. 

The  two  oxides  are  identical  in  constitution  (HgO),  but  the  yellow  is  ob- 
tained by  i)recipitation  from  the  perchloride,  the  red  by  oxidation  of  the  metal 
by  means  of  nitric  acid.  The  red  is  crystalline,  the  yellow  amorphous,  and 
i)C)th  are  i)ractically  insoluble  in  water  and  alcohol,  but  are  soluble  in  acids. 
The  red  oxide  is  liiore  irritant  than  the  ycllow  on  account  of  its  crystalline 
form,  and  perhaps  also  because  it  often  contains  some  nitrate.  The  yellow 
oxide  is  visetl  in  ointment  in  various  diseases  of  the  eye,  and  both  arc  employed 
as  applications  I0  syphilitic  sores,  condylomata  and  chancres,  although  the  red 
is  often  preferreil  for  this  purpose. 


MERCURY  639 

Two  famous  prc])a  rat  ions  of  inorcury  are  the  black  and  tlio  yellow  wasli, 
the  former  prepared  from  calonu^l,  the  latter  from  corrosive  sublimate  by  the 
action  of  lime  water.  The  black  w^ish,  Lotto  Hydrargyri  Nigra  (B.  P.).  con- 
tains mercurous  oxide  (Hg-iO),  the  yellow,  Lotio  Hydrargyri  Flava  (B.  P.), 
mercm-ic  oxide  (HgO).  The  oxides  are  in  both  cases  insolul)le  and  the  lotions 
have  to  be  shaken  before  application.  They  are  used  in  syphilitic  lesions  as 
local  remedies. 

Hydrargyrum  Ammoniaiurn  (U.  S.  P.,  B.  P.),  mercuric  anmionium  chloride, 
white  precipitate  (NH2HgCl),  is  formed  by  precipitating  corrosive  sublimate 
with  ammoniti,  and  is  a  white,  amorphous  ])owder,  without  odor  and  with 
an  earthy,  metallic  taste,  almost  insoluble  in  water  and  alcohol. 

Uiiguentum  Hydrargyri  Ammoniati  (U.  S.  P.),  10  per  cent.,  (B.  P.),  5  percent. 

The  white  precipitate  is  not  used  internally  and  is  more  irritant  than  the 
oxides.  The  ointment  is  occasionally  apphed  in  skin  diseases  and  to  destroy 
parasites. 

Unguentum  Hydrargyri  Nitratis  (U.  S.  P.,  B.  P.),  citrine  ohitment,  is 
used,  diluted  with  oil  or  lard,  in  conjunctivitis,  and  also  as  an  application  to 
syphilitic  sores  and  gangrenous  ulcers;  it  is  acid  and  strongly  irritant. 

Unguentum  Hydrargyri  Citratis  Dihitum  (B.  P.),  citrine  ointment  diluted  to 
one  part  in  five. 

A  large  number  of  new  jjreparations  of  mercury  have  been  introduced  of 
late  years  and  have  received  a  more  or  less  extensive  trial,  but  have  seldom 
been  found  to  be  superior  to  the  older  forms.  Among  these  may  be  mentioned 
the  tannate,  which  was  introduced  in  the  hope  that  it  would  cause  less  purgation 
than  calomel,  and  might  therefore  be  better  adapted  for  the  treatment  of 
syphilis.  0.1-0.3  G.  (2-5  grs.)  in  powder.  The  carbolate,  salicylate  {either 
neutral  or  basic),  benzoate,  sozoiodolate,  thymol-acetate  and  many  other  similar 
compounds  have  been  used  instead  of  calomel  for  hypodermic  or  intramuscular 
injection,  have  each  in  succession  been  blazoned  forth  as  the  best  preparation, 
and  will  probably  be  forgotten  in  the  course  of  a  few  years.  The  salicylate 
preparations  are  said  to  be  excreted  more  rapidly  than  the  inorganic  salts. 
Several  amino-acid  salts  of  mercury  such  as  the  formamide,  the  amino-pro- 
pionate (alanin  mercury)  and  the  s-uccinimide  have  been  proposed  as  substitutes 
for  corrosive  sublimate  in  hypodermic  injection.  It  was  believed  that  the 
affinity  of  mercury  for  nitrogen  being  satisfied  in  these  compounds,  it  would 
attack  the  proteins  less,  and  as  a  matter  of  fact,  the  injections  are  said  to  be 
less  painful  that  those  of  corrosive  sublimate.  Colloid  mercury  ( Hyrgol)^  has 
been  injected  intramuscularly,  but  has  no  advantage  over  the  older  preparations. 
Several  organic  mercury  combinations  in  which  the  metal  is  attached  directly 
to  the  carbon  have  been  formed,  but  have  not  yet  proved  superior  to  the  older 
forms  in  practice. 

Bibliography. 

Chittenden.     Johns  Hopkins  Hosp.,  Bull.,  98,  1899. 

Rosenbach.     Ztschr.  f.  ration.  Med.,  xxxiii,  p.  36. 

Radziejewski.     Arch.  f.  Anat.  u.  Phys.,  1870,  p.  55. 

Heilborn.     Arch.  f.  exp.  Path.  u.  Pharm.,  viii,  p.  361. 

Jendrassik.     Deutsch.  Arch.  f.  klin.  Med.,  xxxviii,  p.  499;  xlvii,  p.  226. 

Bieganski.     Ibid.,  xliii,  p.  177. 

Slintzing.     Ibid.,  xliii,  p.  206. 

Sklodowski.     Ibid.,  Hi,  p.  300. 

Rosenheim.     Zts.  f.  klin.  Med.,  xiv,  p.  170. 

Cohnstein.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxx,  p.  132. 

Justus.     Virchow's  Arch.,  cxl,  p.  91;    cxlviii,  p.  533. 

Kaufmann.     Ibid.,  cxv,  p.  71  and  cxvii,  p.  227. 

Klemperer.     Ibid.,  cxviii,  p.  445. 

Falkenberg  u.  Marchand.     Ibid.,  cxxiii,  p.  579. 

Neuherger.     Ziegler's  Beitrage  zur  path.  Anat.,  vi,  p.  429. 

Wassilieff.     Zts.  f.  phys.  Chcm.,  vi,  p.  112. 

Bohm.      Ibid.,  xv,  p.  1. 


640  THE  HEAVY  METALS 

Welandcr.     Arcli.  f.  Derm.  u.  Syph.,  xxvi,  p.  .331. 

Lewin.     Berl.  klin.  Woch.,  1895.  p.  245. 

Palon.     Brit.  Med.  Journ.,  1886,  i,  p.  4.33. 

Kuperwasser.     Arch,  des  Scicnc.  biol.,  vi,  p.  325. 

WiTitcrnitz.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxv,  p.  225. 

Dreser.     Arch.  f.  exp.  Path.  u.  Pliarni.,  xxxii,  p.  45G. 

Quincke.     Miinch.  med.  Woch.,  xliii,  1896,  p.  854. 

Liebermann.     PfliiKor's  Arch.,  Hv,  p.  573. 

Gcppert.     Berl.  khii.  Woch.,  1889,  p.  789;    1890,  p.  240. 

Gottstcin.     Therap.  Monatsh.,  1889,  p.  102. 

Burgi.     Arch.  f.  Dermat.  u.  Syph.,  Lxxix,  p.  305.  . 

Schumacher.     Arch.  f.  Dermat.  u.  Syph.,  xliv,  p.  189. 

Stockman  and  Chartcris.     Joiirn.  of  Path,  and  Bact.,  1903,  p.  20-1. 

Wickham,  Toulon,  Lieven,  etc.     Practitioner,  July,  1904. 

Bronfenhrcnncr  and  Noguchi.     Journ.  of  Pharmacology,  iv,  p.  333. 

Buchtala.     Zeitschr.  f.  physiol.  Chem.,  Ixxxiii,  p.  249. 

Muller,  Schoeller,  and  Schrauth.     Biochem.  Ztschr.,  xxxiii,  p.  381. 

m.    IRON. 

Iron  differs  from  the  other  heavy  metals  in  being  essential  to  the 
life  of  many,  perhaps  all,  forms  of  protoplasm.  In  the  ^•ertebrates 
this  is  obscured  by  the  fact  that  most  of  the  iron  is  contained  in  the 
hjemoglobin  of  the  blood,  and  its  importance  in  the  other  tissues  is 
generally  ignored.  In  the  invertebrates,  however,  in  many  of  which 
no  corresponding  compound  exists  in  the  blood,  considerable  amounts 
of  iron  are  found  in  the  tissues,  and  there  is  no  question  that  through- 
out the  animal  kingdom  iron  is  essential  to  living  matter,  quite  apart 
from  its  special  relation  to  the  blood  in  the  vertebrates.  Molisch  has 
shown  that  it  is  also  necessary  for  the  development  of  the  lower  vege- 
table forms,  and  it  has  been  found  that  in  its  absence  the  higher  plants 
fail  to  form  chlorophyll,  although  iron  is  not  actually  contained  in  the 
latter  as  it  is  in  haemoglobin. 

The  iron  coml)inations  vary  in  the  readiness  with  which  they  liberate 
the  iron  ion  and  therefore  in  the  facility  with  which  they  react  with 
such  reagents  as  ammonium  sulphide  or  potassium  f errocyanide ;  the 
more  dissociable  salts,  such  as  the  chloride  or  acetate,  are  sometimes 
known  as  "inorganic  iron"  while  compounds  such  as  hamioglobin,  which 
do  not  dissociate  the  iron  ion,  are  termed  masked  or  "organic"  iron; 
l)etween  these  two  extremes  there  lie  many  intermediate  forms,  a\  hich 
react  slowly  to  the  sulphides  and  other  tests. 

The  dissociable  iron  salts  precipitate  proteins  from  solution  and  thus 
act  as  astringents  or  irritants  (page  ()12)  according  to  the  concentration 
in  which  they  are  applied;  but  iron  has  no  specific  poisonous  action 
on  living  matter  such  as  is  possessed  by  mercury  or  antimony,  and  the 
irritation  induced  by  such  salts  as  the  perchloride  arises  from  the  acid 
constituent  and  not  from  the  metal.  The  less  dissociable  compounds, 
such  as  thedouble  salts  and  "organic"  iron,  do  not  precipitate  proteins, 
and  are  therefore  neither  irritant  nor  astringent  as  long  as  they  main- 
tain their  original  form  and  are  not  decomposed  into  simple  salts. 

Symptoms. — Inorganic  iron  compounds,  of  which  the  perchloride 
may  l)e  taken  as  a  type,  have  an  astringent,  metallic,  or  often  acid 
taste,  but  in  ordinary  do.ses  induce  no  further  symptoms.    If  swallowed 


IRON  G41 

in  large  quantities,  they  cause  pain  and  uneasiness  in  the  stoniiich, 
nausea,  voniitint!;  and  often  puri^ing,  with  all  the  ordinary  symptoms 
of  acute  gastro-intestinal  irritation.  (General  weakness  and  e\en 
collapse  may  be  induced,  but  are  manifestly  secondary  to  the  gastric 
and  intestinal  effects,  and  no  symptoms  which  can  in  any  way  be 
attributed  to  the  absorption  of  iron  ha\e  been  observed  in  either  man 
or  animals. 

The  prolonged  use  of  inorganic  iron  is  frequently  followed  by  some 
dyspepsia  and  by  constipation  and  colic,  which  are  obviously  due  to 
the  continued  astringent  action  on  the  stomach  and  bowel.  Other 
symptoms  observed  occasionally  are  blackness  of  the  teeth  and  tender- 
ness in  the  gums,  which  may  be  due  to  the  acid  contained  in  many 
iron  preparations;  the  blackening  of  the  teeth  has  been  supposed  to  be 
due  to  the  tannic  acid  of  the  food  precipitating  the  inky  black  tannate 
of  iron,  or  to  the  sulphide  of  iron  being  formed  by  the  action  of  the 
hydrogen  sulphide  present  in  carious  teeth.  According  to  Buzdygan, 
the  iron  preparations  increase  the  secretion  of  hydrochloric  acid  in 
the  stomach,  and  may  thus  lead  to  hyperacidity,  or  aggravate  it  if 
already  present.  In  artificial  digestion,  the  salts  of  iron  with  organic 
acids  are  said  to  hinder  the  process  more  than  those  with  inorganic 
acids,  the  ferric  salts  more  than  the  ferrous,  and  the  insoluble  prepa- 
rations least  of  all.  The  digestion  of  starch  is  almost  unaffected  by 
the  presence  of  iron. 

Iron  given  by  the  mouth  induces  leucocytosis  (Pohl),  and  does  not 
affect  the  amount  of  double  sulphates  excreted  in  the  urine,  so  that  it 
has  no  antiseptic  action  in  the  bowel  (Morner). 

vSonie  symptoms  from  the  circulation  are  sometimes  said  to  arise,  but  arc 
for  the  most  part  subjective,  and  seem  to  be  handed  down  by  tradition  rather 
than  really  observed.  These  are  a  feehng  of  congestion,  fulness  and  heat  in 
the  head  and  haemorrhages  from  the  nose,  throat  and  lungs,  especially  in 
phthisis.  If  these  symptoms  are  not  entirely  imaginary,  they  are  to  be  attrib- 
uted to  some  reflex  from  the  stomach  and  intestine  and" not  to  any  direct  action 
of  iron  on  the  heart  or  vessels. 

When  these  astringent  preparations  are  injected  into  the  bloodvessels  in 
animals,  they  coagulate  the  proteins  and  cause  thrombosis  Ijut  no  real  symiv 
toms  of  iron  poisoning.  Fatal  thrombosis  has  been  ol)scrved  in  patients  "from 
the  injection  of  the  perchloride  into  the  uterus  and  also  into  nana.  The  hypo- 
dermic injection  of  these  salts  causes  some  pain  and  swelling,  but  no  further 
symptoms  follow,  and  the  iron  is  found  for  the  most  part  deposited  in  an  insoluble 
form  at  the  point  of  injection. 

Tlic  General  Action  of  iron  is  obtained  only  by  the  intravenous  injection 
of  douf^le  salts,  such  as  the  tartrate  of  iron  and  sodium,  which  do  not  cojigulate 
the  blood  and  at  the  same  time  are  capable  of  freeing  the  iron  ion  in  the  tissues. 
Such  salts  as  the  ferrocyanides  or  fcrricyanidcs  on  the  other  hand  leave  the 
body  unchanged,  and  the  iron  ion  is  not  liberated,  so  that  no  iron  symptoms 
are  induced.  Meyer  and  Williams  found  that  the  double  tartrate  caused  in  the 
frog  slowness  and  clumsiness  in  movement,  which  gradually  developed  into 
complete  paralysis  of  the  central  nervous  system.  The  heart  seemed  to  be 
little  affected,  but  the  skeletal  muscles  were  somewhat  less  irritable  than  usual 
after  death.  In  mammals  the  symptoms  of  iron  poisoning  were  often  very 
(ate  in  appearing,  and  began  with  some  acceleration  of  the  breathing,  which 
later  became  slow  and  dyspnoeic;  vomiting  and  diarrhoea  often  followed  and 
41 


642  THE  HEAVY  metals 

1)1(»()<1  was  soinotiiues  seoii  in  the  cvacuatitjiis  of  the  stoniaeh  and  l)o\vel.  Increas- 
ing weakness  was  fohowcd  by  central  ])aralysis  and  death,  accompanied  by 
weak  convnlsive  movements.  The  lieart  seemed  httle  affected,  although  the 
blood-jiressui-e  fell  rapidly  toward  the  end.  Postmortem,  the  mucous  mem- 
branes of  the  stomach  and  intestine  were  found  swollen  and  congested,  and  often 
contain(>d  numerous  small  blood  extravasations.  Robert  found  that  repeated 
injection  of  small  quantities  of  the  citrate  of  iron  induces  congestion  of  the 
kidney  and  the  api)earancc  of  casts  and  albumin  in  the  urine. 

Iron,  like  the  other  heavy  metals,  would  therefore  seem  to  have  a  specific 
irritant  effect  on  the  intestinal  and  gastric  mucous  meml)rane,  and  to  a  less 
extent  on  the  kidney.  In  addition,  it  depresses  and  eventually  paralyzes  the 
central  nervous  system,  but  it  is  impossible  to  state  how  far  this  is  due  to  direct 
action  and  how  far  it  is  secondary  to  the  action  in  the  alimentary  canal. 

Absorption  and  Distribution. — Iron  has  long  been  used  in  the  treat- 
ment of  ana'mia,  more  especially  of  the  form  known  as  chlorosis,  and  it 
was  tacitly  assumed  that  it  was  readily  absorbed  from  the  alimentary 
tract  and  was  utilized  by  the  tissues  to  form  ha?moglobin.  This  view- 
was  contested  by  Bunge  who  held  that  the  therapeutic  action  could  be 
explained  without  assuming  the  absorption  of  iron.  Bunge's  theory, 
which  was  widely  held  for  a  time,  has  now  been  abandoned  even  by  its 
author,  who  has  been  compelled  to  admit  that  the  iron  salts  are  absorbed 
and  that  their  administration  leads  to  an  increased  formation  of  haemo- 
globin. 

The  absorption  of  the  iron  preparations  has  been  shown  both  by  the 
chemical  analysis  of  the  organs  and  by  histological  methods.  The  chief 
difficulties  to  be  overcome  arose  from  iron  being  a  normal  constituent 
of  all  the  tissues  and  from  the  very  small  quantities  that  suffice  to 
maintain  health.  About  2|-3|  G.  (40-55  grs.)  of  iron  are  estimated 
to  be  present  in  the  tissues  of  a  healthy  human  adult,  the  greater  part 
of  it  existing  in  the  form  of  hpemoglobin  in  the  blood.  Formerly  it  was 
belie\ed  that  some  50  mgs.  (1  gr.)  of  iron  were  taken  in  the  food  i)er  day, 
but  Stockman  and  Greig  have  shown  that  this  estimate  is  much  too 
high  and  that  an  ordinary  dietary  provides  only  about  5  10  mgs.  (yV,- 
l  gr.)  of  iron  per  day;  they  found  in  one  case  that  even  3-5  mgs.  (Vo- 
y.j  gr.)  were  sufHclcnt  to  i)reserve  the  iron  equilibrium.  About  the 
same  amount  of  iron  is  excreted  per  day,  chiefly  in  the  fa-ces,  and  to  a 
nnich  smaller  extent  in  the  urin(\ 

When  additional  iron  is  supplied,  the  quantity  in  the  stools  is  greatly 
increased,  while  no  change  is  seen  in  the  iron  of  the  urine.  This  was 
formerly  held  to  show  that  no  iron  was  absorbed  but  this  view  has 
been  proved  erroneous;  for  even  Avhen  a  double  salt  is  injected  intra- 
\-enously,  only  a  trace  is  found  in  the  urine,  and  when  it  reaches  the 
blood  more  slowly  the  proi)ortion  eliminated  in  this  way  falls.  The 
fact  that  an  iron  preparation  gi\en  b\-  tlu>  mouth  does  not  increase  the 
iron  ill  the  urine  is  therefore  no  evidence  that  it  has  not  been  absorbed. 

Iron  injected  into  the  veins  of  iininials  is  stored  up  in  the  liver, 
spleen  and  bone-marrow,  but  is  taken  up  from  these  organs  again,  and 
is  excreted  l)y  the  epithelium  of  the  ca'cum  and  colon.  When  iron  is 
given   by   the   mouth,   therefore,   it  may  either  pass  along  the  canal 


IRON  G43 

and  !)(>  thrown  out  in  tlie  fuecos,  or  it  may  l)e  al)sor])t>(l,  make  a  stay 
ill  the  li\er,  he  excreted  in  the  hirge  intestine,  and  again  aj)pear  in  the 
stools.  The  comparison  of  the  iron  in  the  food  and  in  drugs  Avith  tJiat 
of  the  stools  therefore  gives  no  clue  as  to  how  much  has  been  absorbed 
and  how  much  has  simply  passed  through  the  intestine. 

But  the  passage  of  iron  from  the  liver  to  the  intestine  is  a  somewhat 
slow  process,  ami  it  is  therefore  possible  to  detect  the  excess  of  iron  in 
the  liver.  This  has  been  done  repeatedly  by  the  following  method. 
Young  animals  of  the  same  litter,  fed  on  milk,  have  approximately  the 
same  amount  of  iron  in  the  liver.  If  one  be  fed  on  milk  only,  another 
on  milk  to  which  iron  is  added,  the  Ii\-er  of  the  latter  is  found  to  contain 
more  iron  than  that  of  the  control.  Other  iuAestigators  have  fed 
animals  (rats  or  mice)  on  food  that  is  practically  free  from  iron,  have 
killed  them  and  estimated  the  iron  in  the  whole  body  apart  from  the 
alimentary  tract,  and  compared  it  with  that  of  animals  treated  in  the 
same  way  excei)t  that  iron  was  added  to  the  food.  The  latter  group 
contains  more  iron  than  the  control  group  fed  on  iron-free  food,  and  in 
general  presents  a  more  healthy  and  normal  appearance. 

Finally,  iron  has  been  followed  in  its  course  through  the  tissues 
by  histological  methods,  reagents  being  used  which  color  most  forms  of 
iron,  but  leave  the  haemoglobin  unaffected.  When  animals  are  given 
iron  preparations,  and  are  then  killed  and  their  organs  stained  by  these 
reagents,  the  mucous  membrane  of  the  stomach  and  of  the  greater 
part  of  the  small  intestine  gives  no  coloration,  but  the  epithelium  of  the 
duodenum  and  the  upper  part  of  the  jejunum  is  found  to  contain  numer- 
ous granules  of  iron.  These  granules  may  be  traced  to  the  mesenteric 
lymph  glands,  are  found  in  large  numbers  in  the  spleen  around  the 
corpuscles,  to  a  much  smaller  extent  in  the  liver,  and  in  the  cortex  of  the 
kidney.  If,  however,  the  animal  be  kept  for  some  days  after  the  iron 
is  given,  the  reaction  in  the  duodenum,  spleen  and  mesenteric  glands  is 
less  intense,  while  the  \\\ev  gives  much  more  distinct  evidence  of  con- 
taining iron,  and  the  epithelial  cells  of  the  large  intestine  and  caecum 
also  give  a  strong  reaction.  This  is  interpreted  to  mean  that  iron  is 
absorbed  by  the  duodenum  and  is  first  stored  in  the  spleen,  but  later 
finds  its  way  through  the  bloodvessels  to  the  liver,  where  it  rests  again 
for  some  time,  to  be  eventually  taken  up  again  by  the  blood  and  excreted 
into  the  large  intestine  and  the  caecum.  There  is  some  question  as  to 
whether  the  lymph  vessels  are  involved  in  the  absorption  of  iron,  and 
the  most  recent  investigators  have  failed  to  find  it  in  the  thoracic  duct, 
and  accordingly  hold  that  it  is  absorbed  from  the  intestine  into  the 
bloodvessels  directly.  The  iron  stored  in  the  liver  does  not  escape 
by  the  bile  as  might  be  anticipated.  A  small  percentage  of  iron  is  a 
constant  constituent  of  this  fluid,  but  is  not  increased  by  iron  given 
by  the  mouth  or  intravenously. 

Nothing  is  known  regarding  the  changes  which  the  preparations 
undergo  in  the  stomach  and  intestine  or  the  form  in  which  iron  is 
absorbed;  it  may  be  taken  up  in  solution,  or  may  be  precipitated  and 
taken  up  as  solids  by  the  epithelial  cells  and  the  leucocytes.     In  the 


644  THE  HEAVY   METALS 

liver  it  seems  likely  that  the  ahsorhed  iron  is  changed  to  iiidissociable 
compounds  (ferratin),  several  of  which  have  been  found. 

It  must  not  be  inferred  from  the  foregoinj;  that  all  of  the  inorganic 
iron  swallowed  is  taken  up  by  the  intestinal  epithelium.  It  is  quite 
impossible  to  form  even  approximate  estimates  of  the  amount  that  is 
really  absorbed  and  made  use  of  by  the  tissues,  but  the  proba^  ility 
is  that  only  a  small  percentage  is  really  taken  up;  the  rest  passes 
through  the  intestine  and  is  thrown  out  in  the  stools.  It  is  often 
stated  that  the  iron  stools  are  dark  or  black  in  color,  from  the  sulphide 
present,  but  this  seems  to  be  seldom  the  case  when  the>-  are  passed, 
although  they  assume  a  darker  gray  or  grayish-black  color  in  the  air, 
from  oxidation.  The  iron  is  contained  in  them  only  to  a  small  extent 
as  the  sulphide. 

To  sum  up  what  is  known  regarding  the  fate  of  the  iron  preparations, 
they  probably  undergo  some  changes  in  the  stomach  and  then  pass 
into  the  duodenum,  from  which  the  great  bulk  is  carried  on  into  the 
lower  parts  of  the  intestine,  while  some  is  absorbed  by  the  epithelium 
and  leucocytes  in  solid  form  and  perhaps  in  solution.  It  is  then  deposited 
in  the  spleen,  where  it  may  undergo  some  changes  in  form,  is  later 
taken  up  by  the  blood  and  deposited  in  the  liver  and  perhaps  in  the 
l)one  marrow.  Where  the  supply  of  iron  has  been  inadequate  for  the 
formation  of  htemoglobin,  the  originally  inorganic  iron  is  probably 
worked  into  higher  forms  and  eventually  into  hicmoglobin  in  the  liver, 
and  it  seems  likely  that  ferratin  is  one  of  the  intermediate  steps  in 
this  synthesis.  When  there  is  no  deficiency  of  iron  for  the  formation 
of  h.iemoglobin,  the  liver  slowly  yields  its  store  of  iron  to  the  blood, 
which  carries  it  to  the  crecum  and  large  intestine,  by  the  epithelium 
of  which  it  is  finally  excreted.  It  is  to  be  noted  that  the  iron  absorbed 
does  not  increase  the  amount  of  iron  in  the  urine,  bile,  or  other  excre- 
tions. The  ordinary  preparations  of  iron  follow  the  same  course  in  the 
tissues  as  the  more  complex  compounds  which  exist  in  foods. 

But  this  explanation  of  the  iron  action  does  not  cover  all  the  diffi- 
culties of  the  case.  Many  cases  of  chlorosis  recover  without  inorganic 
iron  under  hygienic  conditions,  such  as  rest,  and  particularly  when 
foods  rich  in  iron  are  prescribed,  this  being  exactly  what  is  to  be  expected 
on  the  theory  that  inorganic  iron  merely  takes  the  i)lace  of  the  deficient 
food-iron.  IJut  many  chlorotic  patients  show  little  or  no  imi>ro\cment 
when  treated  with  foods  containing  iron,  even  when  there  is  no  question 
that  the  iron  supplied  daily  in  food  form  is  sufficient  for  the  needs  of  the 
economy,  and  chlorosis  even  appears  in  individuals  who  have  never 
sull'cred  from  any  deficiency  of  food-iron.  Yet  many  of  these  cases 
recover  rapidly  under  inorganic  iron.  V.  Noorden  has  attempted  to 
explain  this  by  sui)posing  that  inorganic  iron  when  absorbed  acts  as  a 
stimulant  to  the  blood-forming  organs,  while  food-iron  has  no  such 
property.  And  some  indications  of  abnormal  a('ti\ity  of  the  bone- 
marrow  cells  have  been  observed  in  animals  supplied  with  inorganic 
iron;  this  may  not  be  the  eiVect  of  stinndation  in  the  ordinary  sense  of 
the  word,  however,  for  it  may  be  explained  by  the  unusual  abundance 


IRON  645 

of  the  materials  necessary  to  their  activity.  The  difference  in  the  effects 
of  the  irons  of  the  food  and  of  the  inorganic  preparations  may  be  due 
to  the  fact  that  food-iron  is  always  accompanied  by  a  large  amount  of 
colloid  material,  which  may  materially  delay  its  absorption,  while 
inorganic  iron  on  the  other  hand  is  much  less  completely  enveloped, 
and  may  be  more  easily  absorbed.  In  addition,  the  iron  preparations 
are  given  in  much  larger  amounts  than  the  food-irons.  When  10  mgs. 
of  food-iron  are  taken  per  day,  only  a  small  proportion  (e.  g.,  5  mgs.) 
may  be  absorbed,  and  this  may  be  insufficient  to  supply  the  needs  of  the 
body,  but  if  some  hundreds  of  milligrams  of  inorganic  iron  be  added,  the 
proportion  absorbed  will  be  amply  sufficient.  The  same  eflFect  might  be 
obtained  by  the  same  amount  of  food-iron,  but  this  is  only  to  be  obtained 
by  giving  more  food  than  can  be  digested. 

Iron  is  not  absorbed  from  the  unbroken  skin,  and  the  iron  and  steel 
baths  are  therefore  of  no  value  in  themselves  in  the  treatment  of  anaemia. 

No  account  of  the  action  of  iron  would  be  complete,  without  reference  to 
Bunge's  view  which  formerly  attracted  a  large  amount  of  attention,  though  it 
has  now  been  abandoned.  His  theory  was  that  in  ordinary  conditions  a  certain 
amount  of  iron  is  lost  b,y  the  body  constantly  through  the  excretions,  and  tliis 
loss  is  made  up  by  the  absorption  of  the  iron  contained  in  the  food.  This  food- 
iron  consists  wholly  of  organic  iron,  that  is,  of  iron  combined  in  such  a  way  that 
sulphides  attack  it  with  difficulty;  an  example  of  such  organic  iron  is  the 
hsematogen  of  the  yolk  of  egg.  In  normal  individuals  the  food-iron  is  sufficient 
to  replace  that  lost  by  excretion,  but  in  chlorosis  the  presence  of  large  amounts 
of  suljjhides  in  the  intestine  causes  the  food-irons  to  be  decomposed  to  ferric 
sulphide,  which  is  insoluble  and  unabsorbable.  When  the  ordinary  inorganic 
iron  preparations  are  administered  in  these  cases,  they  are  not  taken  up  in  place 
of  the  food-iron;  but,  by  forming  sulphide  in  the  intestine,  they  remove  the 
sulphuretted  hydrogen  and  prevent  the  decomposition  of  the  food-irons,  which 
thus  remain  capable  of  being  absorbed.  Bunge  and  his  followers  went  on  to 
state  that  inorganic  iron  is  never  under  any  circumstances  absorbed  by  the 
normal  epithelium,  but  that  when  large  quantities  are  administered,  they  tend 
to  corrode  the  walls  of  the  stomach  and  intestine,  and  are  thus  absorbed  to  some 
extent.  Even  then,  however,  they  are  incapable  of  being  formed  to  hsemo- 
globin,  the  animal  body  being  able  to  perform  only  the  last  steps  of  this  synthesis 
after  the  plants  have  formed  the  simpler  types  of  organic  iron.  This  theory 
now  possesses  only  historical  interest,  so  that  it  is  unnecessary  to  enumerate  the 
arguments  brought  against  it.  It  may  be  sufficient  to  state  that  if  the  ordinary 
preparations  of  iron  acted  only  by  binding  the  sulphides  of  the  intestine,  various 
other  metals  would  be  equally  efficient  in  chlorosis;  iron  would  not  be  beneficial 
injected  hypodermicallj',  and  iron  sulphide  given  so  as  to  escape  the  action  of  the 
gastric  juice  would  be  equally  useless.  It  is  found,  however,  that  no  other 
metal  can  replace  iron  in  chlorosis;  that  iron  injected  hypodermically  is  curative 
in  chlorosis,  and  that  the  sulphide  administered  so  as  to  reach  the  intestine 
unchanged  acts  as  well  as  other  preparations  (Stockman).  Finally,  it  has  been 
shown  that  ordinary  preparations  of  iron  are  absorbed. 

Therapeutic  Uses. — Iron  is  most  frequently  used  in  the  treatment  of 
Chlorosis,  which  in  a  large  proportion  of  cases  recover  entirely  under 
it.  Some  cases,  however,  improve  somewhat  under  iron,  but  relapse 
when  it  is  left  off,  and  a  certain  number  of  patients  show  no  improve- 
ment whatever  under  it.  These  last  are  not  generally  regarded  as 
suffering  from  chlorosis  proper,  but  from  a  more  malignant  form  of 


G4G  THE  HEAVY  METALS 

ansemia.  Tlie  effects  of  iron  are  seen  in  an  increase  in  the  h.Tmoglobin 
of  the  blood,  while  the  number  of  corpuscles  may  show  little  alteration, 
though  a  considerable  rise  occurs  in  some  cases.  A  number  of  symptoms 
whicli  are  due  to  chlorosis,  and  which  are  often  more  prominent  than  the 
original  disease,  are  also  relieved  or  entirely  removed  by  iron.  Thus 
gastric  catarrh,  amenorrhoea,  or  oedema  may  disappear  under  it,  but  in 
these  cases  the  symptoms  are  chlorotic  in  origin,  and  the  improvement 
is  due  to  the  increased  heemoglobin,  and  not  to  the  direct  action  of  iron 
on  the  stomach,  uterus,  or  circulation. 

In  chlorosis  the  iron  is  generally  given  in  small  doses,  at  anj?^  rate  at 
first,  and  the  less  astringent  preparations  are  preferred  by  most  clinicians, 
although  some  still  advise  the  perchloride.  When  chlorosis  is  compli- 
cated with  gastric  catarrh,  some  authorities  advise  that  the  latter  be 
treated  before  the  general  condition,  as  iron  in  itself  is  liable  to  irritate 
the  stomach.  In  many  cases,  however,  the  catarrh  is  secondary  to  the 
chlorosis,  and  can  only  be  treated  successfully  by  improving  the  con- 
dition of  the  blood;  the  iron  preparation  here  ought  to  be  mild  and  not 
irritating.  In  chlorosis  the  tendency  to  constipation  may  be  increased 
by  iron,  and  a  purge  is  often  required,  such  as  the  iron  and  aloes  pill, 
which  is  particularly  recommended  when  chlorosis  is  attended  by 
amenorrhea. 

Iron  is  of  less  value  in  other  forms  of  ansemia,  although  it  is  often 
prescribed  and  may  be  followed  by  some  improvement.  Thus  it  may 
be  administered  during  convalescence  from  acute  disease,  such  as 
typhoid  fever  or  nephritis,  and  in  the  anaemia  induced  by  profuse 
hjiemorrhage  iron  often  seems  to  accelerate  the  recuperation  of  the 
blood.  It  is  often  prescribed  for  the  cachexia  of  malaria,  syphilis, 
and  other  chronic  diseases. 

Arsenic  is  also  used  in  many  forms  of  anaemia,  but  appears  to  differ 
from  iron  in  accelerating  the  growth  and  renewal  of  the  corpuscles 
rather  than  increasing  their  content  of  haemoglobin.  Both  arsenic 
and  iron  may  be  advisable  in  some  anaemias.  Iron  was  formerly  con- 
sidered to  be  contraindicated  in  fever,  plethora,  heart  disease  and  pul- 
monary phthisis  from  an  apprehension  that  it  tended  to  cause  hannor- 
rhage.  But  there  seems  no  basis  for  this  view.  In  phthisis  it  should  be 
given  with  caution  in  order  to  avoid  irritation  of  the  stomach  and 
dyspepsia,  and  in  the  presence  of  gastric  catarrh  from  any  cause,  its 
effects  have  to  be  watched  carefully. 

Some  of  the  older  authorities  advise  iron  to  be  given  in  large  quan- 
tities, but  the  dose  has  been  reduced  of  late  years  to  about  0.1-0.2 
G.  (2-3  grs.)  three  times  a  day.  It  is  given  after  meals  in  order  to 
avoid  the  irritant  action  on  the  stomach  as  far  as  possible.  It  is  to  be 
noted  that  on  giving  0.1  G.  of  iron  three  times  a  day,  about  thirty 
times  as  much  iron  is  given  as  is  required  normally  in  food,  so  that 
the  chlorotic  receives  more  iron  per  day  than  a  workman  in  a  month. 

Iron  is  occasionally  injected  liy|)odcrmically,  with  XW  object  of 
avoiding  the  irritation  of  the  stomach,  but  this  procedure  is  i)ainful 
and  causes  some  swelling  and  irritation,  which  lasts  tw(Mity-four  hours 


Iron  64? 

or  more.  Most  of  the  salts  are  precipitated  at  the  point  of  injection, 
but  some,  such  as  the  citrate,  are  taken  up  by  the  blood  at  once;  the 
danger  of  renal  irritation,  anticipated  by  Kobert,  does  not  seem  to 
arise  if  small  quantities  are  used;  1-2  grs.  are  injected  in  5  per  cent, 
solution  daily. 

Some  of  the  iron  salts  are  employed  as  Astringents,  the  most  popular 
being  ferrous  sulphate,  which  has  been  used  to  some  extent  in  diarrhoea, 
and  also  externally.  The  perchloride  is  perhaps  the  best  Styptic  of 
its  class.  When  applied  to  a  bleeding  point,  it  precipitates  the  proteins 
of  the  blood  plasma,  and  thus  forms  an  obstruction  to  the  flow  of  blood 
similar  to  that  caused  by  clotting,  although  no  fibrin,  but  only  a  mass 
of  coagulated  protein,  is  formed  by  the  perchloride.  This  styptic  action 
is  of  value  in  capillary  and  recurrent  haemorrhage,  while  in  bleeding 
from  an  artery,  the  ordinary  surgical  methods  are  of  course  preferred. 
The  chloride  arrests  haemorrhage  only  when  it  can  be  brought  into  actual 
contact  with  the  bleeding  point,  and  where  this  is  covered  by  a  large 
mass  of  semicoagulated  blood,  the  treatment  is  of  no  avail,  as  it  simply 
forms  the  precipitate  with  the  blood  with  which  it  comes  into  contact 
first,  and  this  may  be  far  from  the  actual  point  of  rupture.  As  an  appli- 
cation to  the  stomach  and  bowel  in  haemorrhage  from  these  parts,  the 
perchloride  is  unlikely  to  prove  successful,  while  in  bleeding  from  the 
nose,  or  gums,  or  after  the  extraction  of  a  tooth,  it  is  more  reliable. 
It  has  been  injected  into  the  uterus  in  haemorrhage,  into  naevus  in  order 
to  cause  coagulation  and  subsequent  cicatrization  of  the  tissue,  and  into 
aneurisms.  This  is  a  very  dangerous  treatment,  however,  for  several 
cases  of  fatal  embolism  have  arisen  from  the  precipitated  protein  being 
carried  off  in  the  veins.  Perchloride  of  iron  solution  has  been  sprayed 
into  the  air  passages  in  haemoptysis,  but  if  sufficiently  concentrated  to 
coagulate  the  blood  at  the  bleeding  point  in  the  lungs,  it  would  certainly 
induce  irritation  and  coughing.  The  perchloride  is,  of  course,  valueless 
in  haemorrhage  from  internal  organs,  for  in  the  first  place,  very  little 
of  it  is  absorbed,  and  in  the  second  place,  what  does  pass  into  the 
tissues  is  already  in  protein  combination,  and  therefore  incapable  of 
coagulating  the  blood.  The  same  objection  applies  to  the  alleged 
astringent  effect  of  iron  in  nephritis.  It  is  possible  that  iron  may  lessen 
the  albumin  in  the  urine  in  these  cases,  although  the  clinical  evidence 
is  contradictory  on  the  subject,  but  it  is  absolutely  certain  that  it  does 
not  do  so  by  any  local  action  on  the  albumin  in  the  kidney. 

The  sulphate  of  iron  is  used  as  a  disinfectant  for  sewage.  It  acts 
here  merely  by  precipitating  the  proteins,  which  carry  down  the  bacteria 
mechanically.  The  proteins  of  the  sewage  may.  be  increased  by  the 
addition  of  blood  before  the  sulphate  is  applied.  The  sulphate  of  iron 
is  used,  because  it  is  cheaper  than  the  other  salts  of  the  heavy  metals. 

Preparations. 

Ferri  Chloridum  (U.  S.  P.),  ferric  chloride  (FejClc  +  I2H2O),  orange  .yellow 
crystals,  with  a  strong  astringent  taste,  very  deliquescent  in  air,  soluble  in  water 
and  alcohol.    0.065  G.  (1  gr.). 


048  .  THE  HEAVY  METALS 

Liquor  Ferri  Chloridi  (U.  S.  P.),  a  solution  of  ferric  cliloritlc  containing  29 
per  cent,  of  the  anhydrous  salt  or  about  10  per  cent,  of  iron. 

TiNCTUUA  Fkkui  Chlohidi  (U.  H.  p.)  contains  13.28  per  cent,  of  ferric 
chloride,  O.o  c.c.  (8  mins.). 

Liquor  Ferri  Perchloridi  Forlis  (B.  P.)  is  foi-nied  by  dissolving  iron  in  hydro- 
chloric acid  and  contains  20  per  cent,  of  iron.  It  is  an  orange-browii  fluid, 
with  a  strong  astringent  taste. 

Ijiquor  Ferri  I'erehloridi  (13.  P.)  and 

'ri.\L"riH.\  Ferri  Perchloridi  (H.  P.)  contain  about  f)  per  cent,  of  iron. 
Do.se  5-15  mins. 

The  chloride  is  used  as  a  styptic  either  as  the  Liquor  Fortis  (B.  P.)  or  in  a 
vei'y  much  stronger  form,  prepared  by  allowing  the  crystals  to  deliquesce. 
\  plug  of  cotton-wool  steeped  in  the  solution  is  used  to  stop  bleeding  after 
the  extraction  of  teeth,  and  the  liquor  has  been  injected  into  the  uterus  in 
JKcmoi-rhage  and  into  aneurisms  and  luuvi.  When  diluted  it  may  be  used 
as  a  gai'gle,  l)ut  lias  a  disagreeable,  inky  taste,  and  attacks  the  teeth.  The 
tincture  is  very  commonly  used  in  the  treatment  of  chlorosis.  It  ought  to  be 
taken  in  a  glass  of  w'ater,  and  through  a  (juill  or  glass  tube,  in  order  to  avoid 
injury  to  the  teeth. 

Fehhi  SiLPHAs  (U.  S.  P.,  B.  P.),  ferrous  sulphate  (FeS04-}-7H20),  large, 
l);de,  bluish-green  crystals  with  a  saline,  astringent  taste,  soluble  in  water, 
insoluble  in  alcohol,  and  unstable  in  moist  air.    0.2  G.  (3  grs.),  B.  P.  1-5  grs. 

The  sulphate  of  iron  is  very  astringent,  though  less  so  than  the  ferric  salts. 
It  is  used  as  an  astringent  application  to  mucous  membranes,  such  as  the  eye, 
mouth,  urethra,  more  rarely  internally  in  aiuemia,  although  it  is  less  irritant 
than  the  chloride.^ 

The  Pil.  Aloes  et  Ferri  (U.  S.  P.,  B.  P.),  which  is  used  very  largely  in  anienor- 
liio'a  and  in  chlorosis  with  constipation,  contains  dried  sulphate  of  iron.  Dose, 
H.  P.,  4-8  grs. 

Ferrum  Reductum  (U.  S.  P.),  Ferrum  Redactum  (B.  P.),  reduced  iron, 
a  very  fine,  grayish-black,  lustn^less  powder,  without  taste,  insoluble  in  water 
or  alcohol,  solulSle  in  acid.  It  consists  of  metallic  iron,  with  a  small  amount 
of  the  magnetic  oxide.    0.065  G.  (1  gr.) ;  B.  P.,  1-5  grs. 

Ferri  Carbonas  Saccharatus  (U.  S.  P.,  B.  P.),  saccharated  ferrous  car- 
bonate, is  formed  by  precipitating  ferrous  sulphate  wdth  sodium  bicarbonate, 
washing  the  i)recipitatc  and  adding  sugar.  It  contains  ferrous  carbonate  along 
with  some  ferrous  sulphate  and  sodium  bicarbonate,  and  is  a  greenish-brown 
powder,  which  rapidly  oxidizes  in  the  air,  and  has  a  sweetish,  astringent  taste. 
The  carbonate  is  a  very  unstable  body  and  on  keeping  is  slowly  transformed  to 
fei'ric  hydrate  (Fe2(OH)6).  The  sugar  is  added  in  order  to  retard  this  oxidation, 
but  the  carbonate  ought  not  to  be  dispensed  unless  it  is  of  recent  preparation. 
0.25  G.  (4  grs.);  B.  P.,  10-30  grs. 

VuxhM  Ferri  Carbonatis  (U.  8.  P.),  Pilula  Ferri  (B.  P.)  ferruginous 
or  (chalybeate  i)ills,  blaud's  pills,  are  prepared  in  the  same  way,  by  the  action 
of  f(!rrous  suli)hate  and  carbonate  of  i)otash  or  soda.  Sugar,  tragacanth,  and 
glycerin  ai-e  added;  they  ought  to  be  freshly  preinired  in  order  to  avoid  the 
formation  of  the  hydrate.    Dose,  2  pills  U.  S.  P.,  5-15  grs.  B.  P. 

MisTi  ra  Ferri  Composita  (U.  S.  P.,  B.  P.),  (iriffith's  mixture,  is  formed 
by  mixing  ferrous  sulphate,  potassium  carbonate,  and  various  flavoring  sub- 
stances. The  ferrous  carbonate  (FeGO:i)  is  i)recipitated,  and  the  mixture  has 
therefore  to  be  shaken  before  taking,  and  ought  to  be  freshlv  i)repared.  lO  c.c. 
(4  fl.  drs.);  B.  P.,  i-1  fl.  oz. 

Reduced  iron  and  the  four  cai'boiinte  preparations  are  u.sed  exclusively  in 
the  Irealment  of  aiuemia.  They  are  jjractically  devoid  of  iiritant  properties, 
and  are  among  the  best   of  all  the  iron  pn^parations  for  this  ])uri)ose.     'I'he 

'  The  illird  sulpliad-  is  used  to  form  IJlaild'.s  pill.  AiiothiT  sulphate  prcpaiatioii  is 
ll]<'  Liquor  Firri  Siilixuli)liiilis  (I'.  S.  I'.),  or  Moiisi'l's  solution.  \vlii<'h  i.s  supcrHuous. 


IRON  649 

Bland's  Pills  have  in  i)articular  a  well  merited  reputation  in  the  treatment 
of  chlorosis  and  of  ehlorotic  amenorrhtea.  Another  prei)aration  used  for  this 
purpose  but  not  official  is  Ferrum  Dinlysutuni,  in  which  a  considerable  amount 
of  iron  oxide  is  kept  in  a  semi-colloid  state  along  witli  a  mininunn  amount  of 
the  chloride.    It  tastes  of  iron  but' is  not  astringent. 

PlMoi  Feni  lodidi  (U.  S.  P.),  each  contains  0.04  G.  of  iron.    2  pills. 

'Syrupus  Feni  lodidi  (U.  S.  P.,  B.  P.)  contains  about  5  per  cent,  of  the  iodide 
(7  per  cent.  B.  P.).     Dose  1  c.c.  (15  mins.);  B.  P.,  ^-1  fl.  dr. 

These  preparations  have  been  prescribed  to  a  greater  or  less  extent  in  the 
treatment  of  anai'mia.  The  iodide  has  been  advised  in  order  to  combine  the 
effects  of  iodide  and  iron,  but  the  iodide  given  in  this  form  is  in  much  smaller 
quantity  than  that  found  necessaiy  in  the  iodide  of  potassium  treatment,  and 
it  seems  open  to  ciuestion  whether  the  improvement  is  not  due  to  the  iron 

onlv. 

Ferri  et  Quinince  Citras  (U.  S.  P.,  B.  P.),  thin  scales  of  a  reddish-brown  color, 
and  of  a  bitter,  iron  taste,  slowly  solul^le  in  water,  partially  soluble  in  alcojiol, 
containing  11.5  per  cent,  of  quinine  and  13.5  per  cent,  of  iron  U.  S.  P.  0.25  G. 
(4grs.);  B.  P.,  5-10  grs. 

Ferri  et  Ammonii  Citras  (U.  S.  P.,  B.  P.),  thm  garnet-red  scales  with  an 
acid,  iron  taste,  soluble  in  water  and  containing  16  per  cent,  of  iron.  0.25  G. 
(4  grs.);  B.  P.,  3-10  grs. 

These  two  double  salts  of  iron  (scale  preparations)  have  been  used  m  chlorosis 
and  especially  in  convalescence  from  acute  fevers,  which  is  often  accompanied 
by  anaemia.  "  The  iron  is  not  readily  dissociated  and  these  preparations  are 
therefore  not  astringent  and  do  not  disturb  the  digestion.  But  they  are  not 
superior  to  Blaud's  pills  in  this  respect.  Other  similar  preparations  which 
offer  no  advantages  over  these  well-known  scale  preparations  are:  Ferri  et 
Quinince  Citras  Solubilis  (U.  S.  P.),  Ferri  Phosphas  Solubilis  (U.  S.  P.),  Ferri 
Pyrophosphas  Solubilis  (U.  S.  P.),  Ferri  et  Potassii  Tartras  (B.  P.) 

Syrup'us  Ferri,  Quininoi  et  Stnjchnince  Phosphatum  (U.  S.  P.),  Syrupus  Ferri 
Phosphatis  cum  Quinina  et  Strychnina  (B.  P.).    4  c.c.  (|-1  fl.  dr.). 

This  syrup  is  used  as  a  "general  tonic"  and  probably  owes  what  value  it 
possesses  to  the  iron  it  contains.  The  corresponding  glycerite  and  elixir  are 
quite  superfluous. 

Iron  is  contained  in  many  mineral  waters,  which  are  therefore  advised  in 
cases  of  ana?mia.  It  is  generally  in  the  form  of  the  carbonate,  which  is  dis- 
solved by  the  excess  of  carbonic  acid  present,  but  becomes  oxidized  to  the 
insoluble  ferric  hydrate  in  the  air.  The  amount  of  iron  contained  is  small, 
seldom  being  more  than  0.1  G.  per  litre,  but  the  treatment  of  chlorosis  is  un- 
questionably aided  by  change  of  scene  and  in  particular  by  the  high  eleva- 
tions at  which  many  of  these  springs  are  situated,  so  that  the  success  of  treat- 
ment with  these  iron  waters  is  perfectly  intelligible.  Bathing  in  iron  water 
has  no  further  action  on  the  blood  than  ordinary  baths,  as  no  iron  is  absorbed. 

Many  Protein  Compounds  of  iron,  such  as  the  albuminate  and  peptonate, 
have  been  introduced  into  therapeutics,  but  possess  no  advantage  over  the 
usual  preparations,  which  they  resemble  in  their  reactions  to  sulphide  and  other 
tests.  Schmiedeberg  found  in  the  liver  an  iron  compound,  ferratin,  which 
would  seem  to  stand  midway  between  the  ordinary  dissociable  salts  and  haemo- 
globin, for  it  reacts  to  ammonium  sulphide  more  tardily  than  the  former,  while 
the  latter  is  not  affected  by  this  reagent.  Artificial  ferratin,  formed  from 
white  of  egg,  is  not  identical  with  this  hepatic  ferratin  and  is  decomposed  in 
part  in  the  stomach  into  ordinary  salts.  It  is  not  found  to  be  superior  clinically 
to  the  other  milder  preparations  of  iron.  Dose,  0.5-1.5  G.  (8-20  grs.)  per  day, 
in  powder  or  pill  or  in  solution  as  a  sodium  compound. 

Blood  has  been  used  in  therapeutics  by  uncivilized  peoples  since  time  unknown, 
and  has  also  been  recommended  in  motlern  medicine  in  the  treatment  of  chlorosis, 
in  which  it  is  administered  by  the  mouth,  and  also  hypodermically,  though  the 
latter  method  is  difficult  to  carry  out  aseptically.      Ilaiiiuglobin  has  also  been 


650  THE  HEAVY   METALS 

advertised  largely  of  late  years  in  a  more  or  less  impure  form.  In  the  stomach, 
haMuoglobin,  whether  contained  in  blood  or  as  crystals,  is  changed  to  ha'matin; 
Abderhalden  found  that  both  luTmoglobin  and  haematin  are  absorbed  and  lead 
to  an  increase  in  the  haemoglobin  of  the  blood. 

On  the  whole,  these  new  iron  preparations  have  httle  to  recommend  them 
as  superior  to  the  older  ones  and  are  therefore  superfluous. 

Bibliography. 

Meyer  u.  Williams.     Arch.  f.  exp.  Path.  u.  Pharm.,  xiii,  p.  70. 

Robert.     Ibid,  xvi,  p.  361. 

Bunge.     Ztschr.  f.  phys.  Chem.,  ix,  p.  49;   xiii,  p.  399;    xvi,  p.  173;    xvii,  p.  03 

Hausermann.     Ibid,  xxiii,  p.  555. 

Marfori.     Arch.  f.  exp.  Path.  u.  Pharm.,   xxix,  p.  212. 

Schmiedeherg.     Ibid.,  xxx:iii,  p.  101. 

Gottlieb.     Ibid.,  xxvi,  p.  139;  Zts.  f.  phys.  Chem.,  xv,  p.  371. 

Jakoby.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxviii,  p.  256. 

Socin.     Zts.  f.  phys.  Chem.,  xv,  p.  93. 

Molisch.     Sitzungsber.  Wien.  Akad.,  ciii,  1894,  Abt.  i,  p.  554. 

Kunkel.     Pflliger's  Arch.,  1,  p.  1;   Ixi,  p.  595. 

Stockman.  Brit.  Med.  Journ.,  1893,  i,  p.  881;  Journ.  of  Phys.,  xviii,  p.  484;  xxi, 
p.  55  (with  Greig). 

McCallum.     Journ.  of  Phys.,  xvi,  p.  268;   xxii,  p.  92. 

Woltering.     Ztschr.  f.  phys.  Chem.,  xxi,  p.  186. 

Hall.     Arch.  f.  Anat.  u.  Phys.,  1894,  p.  455;    1896.  p.  49. 

Pohl.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxv,  p.  65. 

Hochhaus  u.  Quincke.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxvii,  p.  159. 

Damaskin,  Kumberg,  Busch,  Slender,  Anselm,  Samojloff.  Arb.  a.  d.  pharm.  Instit.  zu 
Dorpat,  vii,  viii,  ix. 

Cloetta.     Arch.  f.  exp.  Path.,  xxxvii,  p.  69;    xxxviii,  p.  161;    xliv,  p.  363. 

Hofmann.     Virchow's  Arch.,  cli,  p.  488;    clx,  p.  235. 

Filippi.     Ziegler's  Beitrage  zur  path.  Anat.,  xvi,  p.  462. 

Momer.     Zts.  f.  phys.  Chem.,  xviii,  p.  13. 

Buzdygan.     Wien.  khn.  Woch.,  1897,  p.  713. 

Voit.     Zts.  f.  Biol.,  N.  F.,  1893,  xi,  p.  387. 

Baumann.     Journ.  of  Phys.,  xxix,  p.  18. 

Tartakowsky.     Pfluger's  Arch.,  ci,  p.  423. 

V.  Noorden.     Berl.  klin.  Woch.,  1895,  p.  181. 

Hari.     Arch.  f.  Verdauungskrank.,  iv,  p.  160. 

Abderfialden.     Ztschr.  f.  Biologic,  xxxix,  pp.  113,  193.  4S7 

Mailer.     Virchow's  Arch.,  clxiv,  p.  436. 


IV.    LEAD. 

Lead  is  used  to  some  extent  in  therapeutics,  but  its  chief  interest 
from  a  medical  point  of  view  lies  in  the  frequency  with  which  it  gives 
rise  to  chronic  poisoning,  and  in  the  diversity  of  the  symptoms  pre- 
sented in  that  condition. 

Solutions  of  lead  salts  precipitate  proteins,  and  this  precipitate  is 
formed  when  lead  solutions  are  applied  to  the  mucous  membranes  a,nd 
jjrotects  them.  The  metal  contained  in  the  precipitate  is  not  destructive 
to  the  cells  as  in  the  case  of  mercury,  so  that  the  lead  salts  are  less 
corrosive;  and  the  salts  chiefly  used  are  the  acetates,  whose  acid  is 
only  slightly  active,  so  that  the  astringent  action  of  the  protein  pre- 
cipitate is  the  chief  feature  of  the  action.  Solutions  of  lead  nitrate  arc 
irritating  and  corrosive,  liDWcver,  bccmisc  it  is  more  readily  dissociated 
and  the  nitric  acid  freed  is  itself  corrosive. 


LEAD  051 

Symptoms.  —  In  ordinary  therapeutic  doses,  the  acetate  of  lead 
(sugar  of  lead)  has  a  sweetish,  metaUic  taste  followed  by  a  feeling  of 
astringency,  and  induces  no  symptoms  except  constipation.  The 
stools  after  lead  are  often  said  to  be  dark  in  color  from  the  sulphide 
formed  in  the  intestine,  but  this  does  not  seem  to  be  the  general  rule. 
Probably  little  lead  is  absorbed  from  an  ordinary  dose  of  the  acetate; 
at  any  rate  no  symptoms  arise  from  the  general  action  of  the  metal 
absorbed. 

Lead  acetate  solutions  applied  to  the  skin  have  no  effect,  but  mucous 
membranes,  or  exposed  tissues,  such  as  ulcers,  are  covered  with  a  thin 
pellicle  of  precipitate,  which  serves  to  protect  them  from  irritation, 
and  thus  promotes  their  healing. 

When  very  large  quantities  of  acetate  are  swallowed,  particularly  if 
in  a  concentrated  form,  they  give  rise  to  the  ordinary  symptoms  of 
irritant  poisoning,  nausea,  vomiting,  pain  in  the  abdomen,  violent 
purging  or  sometimes  constipation,  blood  in  the  vomited  matter  and 
stools,  great  thirst,  weakness,  and  collapse.  In  some  instances  in  wdiich 
the  patients  recovered  from  these  symptoms,  they  subsequently  suffered 
from  chronic  lead  poisoning,  but  apart  from  these,  nothing  'in  the 
course  of  acute  lead  poisoning  suggests  the  absorption  of  the  metal, 
all  the  symptoms  being  obviously  due  to  the  local  effects  on  the  stomach 
and  bowel,  and  to  the  consequent  collapse.  In  fact  the  effects  of  a 
sudden  absorption  of  lead  in  man  are  unknown. 

In  animals  also,  some  difficulty  has  been  met  in  inducing  the  symptoms 
due  to  the  action  of  large  quantities  of  lead  in  the  tissues,  because  most  forms 
of  lead  injected  into  the  vessels  precipitate  the  proteins  of  the  blood  and  cause 
embolism,  while,  on  the  other  hand,  only  local  symptoms  can  be  induced  by 
its  administration  by  the  mouth.  Hamack  injected  salts  of  lead-triethyl,  in 
which  the  metal  is  not  contained  in  a  dissociable  form,  but  which  is  decom- 
posed in  the  tissues  and  then  gives  rise  to  lead  sjanptoms.  In  the  frog  it  induced 
general  paralysis,  apparently  from  direct  action  on  the  central  nervous  system. 
The  frog's  muscle  is  also  affected  by  lead,  as  is  shown  by  changes  in  its  elasticity 
and  irritabiUty  and  by  changes  in  the  form  of  the  curve  of  contraction  (Cash). 
In  the  dog  large  doses  of  lead  injected  into  a  vein  induce  weakness  and  para- 
lysis, violent  diarrhoea  and  cohc,  chorea-like  movements,  tremors,  which  often 
assume  the  appearance  of  true  convulsions,  and  ataxia.  The  diarrhoea  Harnack 
found  to  be  due  to  violent  contractions  of  the  intestinal  walls,  which  main- 
tained a  certain  degree  of  contraction  even  when  no  peristaltic  wave  was  passing. 
This  action  of  lead  upon  the  intestine  is  of  interest,  because  it  bears  a  close 
relation  to  the  colic  observed  in  chronic  lead  poisoning  in  man,  although  here 
there  is  generally  constipation,  and  also  because  it  connects  lead  with  the  other 
heavy  metals,  all  of  which  have  more  or  less  specific  action  on  the  intestine. 
The  ataxia  and  other  brain  symptoms  also,  have  their  counterpart  in  the  brain 
symptoms  of  chronic  poisoning  in  man. 

A  single  dose  of  a  lead  salt  does  not  generally  give  rise  to  any 
symptoms  wdiich  would  indicate  the  absorption  of  the  metal,  but  the 
continued  ingestion  of  small  quantities  by  way  of  the  stomach,  or 
by  inhalation  by  the  lungs,  induces  chronic  poisoning,  which  can  be 
explained  only  by  its  absorption.  There  seems  some  reason  to  believe 
that  lead  is  absorbed  from  the  unbroken  skin,  though  it  is  possible 


652  THE  HEAVY  METALS 

that  some  of  the  metal  was  carried  to  the  mouth  and  swallowed  with 
the  food  ill  tiie  cases  on  which  the  statement  is  founded.  Lead  is 
apparently  Absorbed  more  rapidly  than  most  of  the  metals  except 
mercury,  and  remains  lodged  in  the  tissues  a  long  time,  the  excretion 
taking  ])lace  only  very  slowly.  It  is  found  in  most  organs  in  cases  of 
poisoning,  i)articularly  in  the  liver  and  kidney.  It  is  Excreted  in  the 
urine,  the  bile,  the  secretion  of  the  intestinal  epithelium,  in  the  milk 
and  saliva,  and  in  traces  in  the  perspiration. 

Chronic  Lead  Poisoning  is  the  commonest  of  all  forms  of  metallic 
poisoning,  and  at  the  same  time  one  of  the  most  insidious.  It  is  always 
accidental,  and  although  it  is  most  common  in  workers  in  lead,  may 
occur  in  persons  who  are  not  apparently  liable  to  come  in  contact 
with  the  metal.  There  is  no  question  that  some  people  are  much  more 
susceptible  to  lead  than  others  and  that  a  certain  tolerance  is  developed 
in  some  instances,  persons  who  suffered  from  the  early  symptoms 
recovering  and  proving  resistant  to  the  further  action  of  the  metal. 
Ansemia  and  weakness  from  any  cause  are  generally  believed  to  pre- 
dispose to  the  disease,  w^omen  and  children  are  more  liable  to  it  than 
men,  and  alcoholism  and  previous  lead  intoxication  increase  the  tendency 
to  the  attack.  Relapses  are  very  common,  and  may  occur  years  after 
the  first  symptoms,  even  although  there  has  been  no  further  exposure 
in  the  interval.  Lead  smelters,  workers  in  white  lead  factories,  painters, 
plumbers,  electricians,  and  typesetters  are  liable  to  lead  poisoning 
from  continually  handling  the  metal;  but  other  trades  are  not  exempt 
from  it,  and  sometimes  the  channels  by  which  it  gains  entrance  to  the 
body  are  very  obscure.  Some  of  the  more  common  causes  of  poisoning 
are  lead  water-pipes  or  cooking  utensils,  lead  used  to  close  tins  of  meat 
or  fruit,  and  lead  in  hair  dyes.  Formerly  a  common  source  of  poisoning 
was  wine  and  cider  to  which  lead  had  been  added  to.  reduce  the  acidity. 
A  considerable  number  of  cases  of  poisoning  ha\-e  l)een  recorded  from 
the  use  of  lead  preparations  as  abortifacients. 

The  symptoms  of  chronic  lead  poisoning  vary  greatly  in  difYerent 
cases,  sometimes  only  one  or  two  organs  being  attacked,  in  others  the 
whole  economy  appearing  invohed  in  the  disorder.  The  symjitoms 
may  be  divided  into  groups  for  convenience,  but  it  is  to  be  noted  that 
many  of  these  appear  to  be  closely  inter-connected,  and  that  in  many 
cases  it  is  imi)ossible  to  decide  whether  a  set  of  symptoms  is  due  to 
direct  action  upon  a  single  organ,  or  to  the  siiuultancous  disease  of 
several. 

The  Mouth,  Stomach  and  Digestion  \ery  often  give  early  indications 
of  lead  j)()isoniiig.  The  patient  complains  of  loss  of  appetite,  nausea, 
constipation,  wasting,  a  metallic  taste  and  foetid  breath,  and  a  blue- 
black  line  is  seen  along  the  margin  of  the  teeth  where  they  enter  the 
gums.  This  "lead  line"  is  due  to  the  precipitation  of  lead  sulphide 
by  the  hydrogen  sulphide  arising  from  septic  processes  in  the  teeth  and 
gums;  it  is  often  absent  if  the  teeth  and  mouth  are  kept  clean  and 
healthy,  and  its  i)resence  does  not  indicate  lead  iKiisoning,  but  only 
contact  witli  lead.     The  metallic  taste  seems  due  to  the  excretion  of 


LEAD  653 

lead  in  tlic  saliva,  and  the  loss  of  ai)i)i'tite  may  arise  from  tlie  same 
canse.    These  symptoms  may  be  produced  in  animals  also. 

Another  early  symptom  is  Anaemia,  which  may  be  due  in  part  to 
malnutrition,  but  is  attributed  mainly  to  an  abnormal  destruction  of 
the  red  cells  of  the  blood;  the  white  corpuscles  are  increased  in  many 
cases  but  not  in  all.  It  is  often  accompanied  by  jaundice,  with  the 
highly  pigmented  urine  and  other  symptoms  which  usually  follow  the 
liberation  of  large  quantities  of  haemoglobin  from  the  breaking  up  of 
red  cells.  The  red-blood  cells  often  contain  granules  staining  with 
basophile  dyes  and  indicating  incomplete  disappearance  of  the  nucleus; 
this  change  may  present  itself  before  any  other  symptom  but  occurs 
also  in  other  forms  of  anaemia.  The  anaemia  is  often  very  marked, 
and  is  sometimes  the  chief  or  only  symptom  of  lead  poisoning;  according 
to  some  authorities,  it  is  present  in  a  greater  or  less  degree  in  the  majority 
of  white-lead  workers,  and  it  leads  to  weakness,  languor,  and  in  }'oung 
women  often  to  amenorrhoea.  Abortion  is  very  often  met  with  in  lead 
poisoning,  and  in  women  employed  in  lead  works  who  do  not  show  any 
marked  symptoms  of  disease.  The  children  of  parents  sufTering  from 
lead  are  often  weak  and  undersized,  and  a  very  large  proportion  of  them 
die  in  early  infancy. 

One  of  the  commonest  symptoms  is  Lead  Colic,  painters'  colic,  colica 
saturnina  or  colica  Pictonum.  This  generally  sets  in  suddenly,  and 
is  accompanied  in  most  cases  by  obstinate  constipation,  in  a  ver}^  small 
proportion  by  diarrhoea.  Paroxysms  of  the  most  acute  agony  are 
followed  by  intervals  of  comparative  freedom  from  pain,  but  in  these 
'intervals  some  tenderness  of  the  abdomen  may  be  complained  of, 
while  during  the  attack  ])ressure  generally  relieves  the  pain.  The  colic 
lasts  for  several  days,  or  a  w^eek,  and  then  disappears,  but  is  liable 
to  return  at  intervals.  The  abdomen  is  generally  hollow,  retracted 
and  hard,  and  during  the  acute  spasms  the  patient  often  gains  some 
relief  by  lying  on  his  face  with  the  fists  pressed  against  the  umbilical 
region,  to  which  the  pain  is  usually  referred.  Vomiting  is  frequently 
present,  the  pulse  is  slow  and  very  hard,  especially  during  the  acute 
crises,  while  the  respiration  may  be  accelerated.  The  urine  is  scanty 
and  often  contains  haematoporphyrin. 

The  cause  of  lead  colic  is  evidently  spasm  of  the  intestine,  but  it  is 
uncertain  whether  it  arises  from  action  on  the  muscle  or  on  the  gang- 
lionic plexus.  It  can  be  induced  in  animals,  and  is  relieved  by  atropine. 
The  blood-pressure  is  raised  in  man,  not  only  during  the  spasms,  but 
also  in  the  intervals.  This  contraction  of  the  vessels,  like  the  slowing 
of  the  pulse,  is  often  said  to  be  reflex  from  the  pain,  but  this  seems  to 
l)e  disproved  by  the  fact  that  it  remains  during  the  intervals.  Some 
writers  have  therefore  regarded  the  colic  and  its  attendant  symptoms 
as  due  to  a  vascular  spasm,  and  have  supported  this  by  showing  that 
nitrite  of  amyl,  which  dilates  the  vessels,  also  relieves  the  colic. 

Another  common  result  of  chronic  lead  poisoning  is  Paralysis,  lead 
or  painters'  palsy,  paralysis  saturnina,  which  is  almost  invariably 
limited  to  certain  groups  of  muscles,  the  extensors  of  the  forearm. 


654  THE  HEAVY  METALS 

It  is  bilateral  in  many  cases,  but  sometimes  involves  only  one  arm. 
The  affection  <,fenerally  bejjins  in  the  middle  and  ring  finf^ers,  which 
cannot  be  extended,  then  spreads  to  the  index  and  little  finfjer,  and 
afterward  to  the  thumb  and  wrist.  The  fingers  remain  iiexed  and  later 
the  wrist  is  similarly  affected,  so  that  the  condition  is  often  known  as 
wrist-drop.  Pvven  after  all  the  other  muscles  of  the  extensor  surface  of 
the  forearm  are  involved,  the  supinator  longus  remains  normal  as  a 
general  rule.  The  muscles  affected  atrophy  rapidly,  and  in  old  cases 
contracture  of  the  flexor  muscles  sets  in,  when  the  limb  becomes  im- 
movable and  has  a  characteristic  claw-like  appearance.  INIore  rarely 
other  regions  are  affected,  such  as  the  laryngeal  muscles  (in  the  horse), 
the  external  rectus  of  the  eye,  or  the  muscles  of  the  leg.  In  animals 
several  observers  have  succeeded  in  inducing  paralysis  of  the  hind 
limbs,  and  the  legs  are  said  to  be  affected  very  often  in  young  children. 
When  paralysis  is  complete,  the  reaction  of  degeneration  is  given  by  the 
muscles  on  electric  stimulation,  and  even  muscles  which  are  not  com- 
pletely paralyzed  are  said  to  give  it  in  some  cases.  The  cause  of  lead 
palsy  is  peripheral  neuritis  and  degeneration  of  the  nerves,  which 
sometimes  involves  secondarily  the  cells  of  the  anterior  horn  of  the 
spinal  cord.  Peripheral  neiiritis  and  paralysis  have  been  elicited 
repeatedly  in  animals.  According  to  Edinger's  view  the  nerves  of  those 
muscles  are  selected  by  lead,  which  are  least  developed  in  proi)ortion  to 
the  work  they  have  to  perform.  The  afferent  fibres  are  also  involved 
in  the  action,  as  is  shown  by  local  Ansesthesia,  which  is  generally  sudden 
in  its  onset,  but  may  be  preceded  by  numl)ness  or  tickling  of  the  skin, 
and  generally  lasts  only  one  or  two  weeks  when  sensation  returns 
again  to  the  part. 

Lead  Arthralgia,  which  arises  from  the  same  action  on  the  peripheral 
nerves,  consists  in  sharp  lancinating  or  boring  i)ains  around  the  joints, 
the  intensity  of  the  pain  l)eing  comparable  only  to  that  of  lead  colic. 
It  sets  in  suddenly,  usually  in  the  night,  and  generally  disappears  as 
suddenly. 

Lead  Amblyopia,  or  bhndness,  is  one  of  the  rarer  affections.  The 
sight  may  l)e  lost  completely,  or  may  only  be  dim,  and  the  onset  may 
be  sudden  or  gradual.  It  arises  from  neuritis  of  the  oj^tic  ner\e  and 
degeneration  of  the  retinal  nerve  cells,  or  in  some  cases  may  be  the 
result  of  the  changes  in  the  kidney  occasioning  albuminuric  retinitis 
or  effusion  into  the  optic  sheath.  In  early  cases  of  neuritis,  the  disease 
can  generally  be  arrested  and  even  c()m])lete  restitution  may  take  ])liu-e, 
but  if  it  is  neglected,  optic  atrophy  follows. 

Under  saturnine  Encephalopathia,  a  number  of  disorders  of  the 
})rain  are  classed  together.  They  are  com])aratively  rare  at  the 
present  time,  and  their  onset  generally-  indicates  long  standing  and 
neglected  lead  intoxication,  although  in  some  cases  the  ])atient  has 
been  exposed  to  the  poison  for  only  a  short  period.  One  of  the  most 
characteristic  features  is  the  rapidity  with  which  the  disease  changes 
from  one  type  to  another,  and  the  diversity  of  the  symptoms  present 
at  one  time.     These  cerebral  symptoms  sometimes  apjjcar  suddenly. 


LEAD  655 

while  ill  other  cases  tiiey  are  herakk'd  by  viok>ut  headache,  giddiness 
and  sleeplessness,  or  by  amblyopia,  deafness,  great  depression,  stupor, 
weakness,  and  tremor.  Later,  sudden  mania  and  delirium,  with  con- 
vulsions resembling  chorea  or  epilepsy,  hallucinations  and  illusions 
indistinguishable  from  those  of  alcoholic  delirium,  sudden  apoplectic 
paralysis,  ataxia,  partial  analgesia,  hypersesthesia,  or  coma  may  occur 
separately  or  in  succession.  Oliver  states  that  the  encephalopathic 
symptoms  are  especially  liable  to  occur  in  persons  addicted  to  alcohol. 

In  animals  cerebral  symptoms  are  readily  induced  by  lead,  either 
by  intravenous  injection  (Harnack),  or  by  chronic  poisoning  with  the 
ordinary  salts.  Chorea,  tremors  and  general  convulsions  have  been 
caused  in  this  way  in  dogs. 

The  encephalopathia  is  obviously  of  cerebral  origin  for  the  most 
part,  although  the  lower  divisions  of  the  central  nervous  system  are 
also  involved  in  many  cases.  In  several  autoposies  of  patients  dying 
from  lead  poisoning,  atrophy  of  parts  of  the  cerebrum,  or  haemor- 
rhages have  been  found,  and  very  frequently  disease  of  the  brain 
vessels  has  been  met  with.  In  other  cases  of  undoubted  encephalo- 
pathia in  man,  no  such  lesions  have  been  observed,  and  in  animals 
poisoned  by  Harnack's  method  they  are  certainly  not  present.  Many 
of  the  symptoms  are  obviously  not  due  to  these  gross  lesions,  for  the 
suddenness  of  their  onset  and  of  the  recovery  precludes  any  such 
explanation,  and  shows  that  lead  has  also  a  direct  action  on  the  brain 
cells. 

It  must  be  noted  that  in  addition  to  these  generally  recognized 
symptoms  of  encephalopathia  saturnina,  several  obscure  chronic 
nervous  diseases  have  been  ascribed  by  Putnam  and  others  to  lead 
intoxication,  and  it  is  certainly  possible  that  its  action  may  prove  to 
be  even  more  wide-reaching  and  insidious  than  is  generally  recognized 
at  present. 

Another  organ  acted  on  by  lead,  especially  in  prolonged  poisoning, 
is  the  Kidney,  which  is  often  found  to  present  a  typical  red  granular 
nephritis.  During  life  the  urine  presents  the  ordinary  appearances 
of  this  disease,  being  copious  in  amount  and  of  low  specific  gravity, 
and  containing  comparatively  small  quantities  of  albumin  or  casts. 
In  some  cases  in  man,  the  kidney  has  presented  a  mixture  of  paren- 
chymatous and  interstitial  disease,  while  in  animals  the  parenchyma 
alone  is  affected,  perhaps  because  the  experiments  have  not  lasted  long 
enough.  The  disease  of  the  kidney  from  lead  poisoning,  as  from  other 
sources,  may  cause  dropsy,  ursemia  and  amblyopia,  but  the  brain  and 
eye  may  be  affected  in  cases  in  which  there  is  no  nephritis. 

Gout  is  very  common  in  lead  poisoning,  which  evidently  predisposes 
to  this  disease,  if  it  does  not  actually  cause  it,  for  Garrod  states  that 
in  one-fourth  of  the  cases  of  gout  treated  by  him  there  was  a  history 
of  lead  poisoning.  In  districts  where  ordinary  gout  is  rare,  lead  poison- 
ing seldom  leads  to  it,  but  where  ordinary  gout  is  met  with,  it  is  a 
fairly  common  complication  of  saturninism.  The  purine  substances 
of  the  urine  are  augmented  in  chronic  lead  poisoning  in  animals. 


656  THE   HEAVY   METALS 

Another  condition  in  whicli  load  i)oisoning  may  act  as  a  predisposing 
factor  is  Arteriosclerosis;  the  nialnntrition,  ana'mia,  and  renal  changes 
indnced  l)y  th(>  metal  wonld  in  themselves  tend  to  indnce  changes  in  the 
vessels  thronghout  the  body,  and  degeneration  of  their  walls  is  met 
with  in  a  considerable  proportion  of  cases  of  very  prolonged  exposure 
to  it. 

Lead  ])ois()ning  runs  no  definite  course.  As  a  general  rule  the  anaemia, 
wasting,  consti])ation  and  weakness  appear  early,  and  then  colic  may 
follow,  or  paralysis,  or  arthralgia.  Nephritis,  encephalopathia,  anaes- 
thesia and  gout  are  rarer,  and  as  a  rule  occur  only  in  very  prolonged 
])oisoning.  An\'  one  of  these  symptoms  may  be  present  alone,  and  the 
diagnosis  is  then  very  difficult.  In  doubtful  cases  the  urine  or  the 
stools  may  be  tested  for  lead.  Every  case  in  which  lead  is  found  in  the 
urine  is  not  necessarily  one  of  lead  intoxication,  however,  for  it  has  been 
detected  in  a  number  of  perfectly  healthy  individuals. 

It  is  impossible  at  present  to  give  any  general  explanation  for  the 
diversity  of  the  forms  of  chronic  lead  poisoning.  The  central  nervous 
system  is  certainly  acted  on,  both  in  its  higher  and  lower  divisions. 
The  lead  line,  metallic  taste  and  nausea,  and  perhaps  the  constipation, 
would  seem  to  be  connected  with  the  excretion  of  the  metal  along  the 
alimentary  canal,  while  the  renal  action  is  probably  of  the  same  nature 
as  that  inducing  periarteritis  in  the  brain  and,  as  is  alleged,  in  the 
lungs  under  some  conditions.^  The  anaemia  indicates  an  action  on  the 
red  cells  of  the  blood,  and  the  gout  some  disturbance  of  the  general 
nutrition.  Attempts  ha\e  been  made  to  elucidate  the  nature  of  this 
action  on  metabolism  by  estimating  the  urea  and  other  constituents  of 
the  urine,  but  no  important  light  has  been  thrown  on  it  by  this  means, 
nor  in  fact  are  significant  riesults  to  be  hoped  for  in  a  disease  which 
offers  so  many  and  so  diverse  t^T^es  as  lead  poisoning.  In  chronic  poison- 
ing lead  is  found  deposited  in  the  liver  and  other  organs,  l)ut  the  quantity 
actually  in  circulation  at  any  one  time  may  be  so  small  as  to  entirely 
escape  estimation;  the  symptoms  and  lesions  of  chronic  lead  poisoning 
are  thus  not  due  to  the  accumulation  of  lead  in  the  affected  organs  but 
to  the  cunuilation  of  injury  from  its  continually  renewed  passage  in 
infinitesimal  dilution  (Straub). 

Lead  acts  upon  so  many  tissues  that  it  might  be  exi)ected  to  ha\e 
some  distinctive  action  upon  the  simpler  organisms,  but,  as  a  matter 
of  fact,  it  seems  less  poisonous  to  them  than  most  other  heavy  metals. 


Preparations. 

Pumn  AcETAS  (U.  S.  P.,  B.  P.),  load  acetate,  sugar  of  lead  (PbCCjlLO.), 
+  :in2()),  forms  colorless  crystals,  with  a  sweetish,  astringent,  afterward  niojallic 
taste,  very  .soluble  in  water,  less  so  in  nleohol.    O.Ot);")  {\.  (1  gr.);   B.  P.,  1-5  grg. 

'  Some  authorities  are  disposed  to  regard  the  action  on  the  vessels  as  the  fundamental 
feature  in  lead  poisoning  which  leads  to  all  the  oth(  r  symptoms;  thus  the  colic  is  said  to 
lie  a  vascular  spasm  and  tlu^  (-iicei)hal()p:i11iia  and  palsy  to  arise  from  capillary  hemor- 
rhages. 


LEAD  057 

Suppositoria  Plumbi  Composita  (B.  P.);  each  contains  3  grs.  of  lead  acetate 
and  1  gr.  of  opium. 

Pihda  Plumbi  cum  Opio  (B.  P.),  contains  about  12  per  cent,  of  opium. 
2-4  grs. 

Liquor  Plumbi  Svhacetatis  (U.  S.  P.),  Liquor  Plumbi  Subacetatis  Fortis  (B.  P.), 
Goulard's  extract,  an  aqueous  solution  containing  about  25  per  cent,  of  lead 
subacetate  (approximately  Pb(C2H302)2PbO).  When  exposed  to  the  air,  the 
insoluble  lead  carbonate  is  formed.  The  subacetate  solutions  are  alkaline  in 
reaction. 

Liquor  Plumbi  Subacetatis  Dilutus  (U.  S.  P.,  B.  P.),  lead  water,  Goulard's 
lotion  or  water,  a  solution  containing  about  1  per  cent,  of  the  subacetate. 

Glycerinum  Plumbi  Subacetatis  (B.  P.). 

Unguentum  Plumbi  Subacetatis  (B.  P.). 

Lead  plaster  or  diachylon  plaster,  Emplastrum  Plumbi.    (See  Part  IV.) 

Therapeutic  Uses. — Lead  is  used  in  therapeutics  only  for  its  astrin- 
gent action.  The  acetate  is  prescribed  internally  in  diarrhoea,  generally 
along  with  opium,  and  always  in  pill  form,  as  the  solution  would  act 
on  the  stomach  and  have  less  effect  on  the  bowel.  It  has  been  tried 
in  dysentery  and  cholera,  but  has  proved  of  little  value.  Lead  has 
also  been  advised  in  cases  of  haemorrhage  from  the  lungs,  kidneys  and 
uterus,  but  is  quite  valueless  here,  as  it  acts  as  a  st^q^tic  only  when 
applied  locally.  Still  less  reason  is  there  for  its  use  in  nephritis,  cystitis, 
and  similar  conditions. 

Externally,  a  solution  of  the  acetate  or  the  dilute  solution  of  the 
subacetate  is  used  as  an  astringent  lotion  in  burns  and  as  an  injection 
in  gonorrhoea. 

Lead  ought  not  to  be  employed  externally  or  internally  except  for 
a  short  time  as  otherwise  symptoms  of  poisoning  may  arise. 

Poisoning. — In  acute  lead  poisoning,  the  indications  are  its  removal 
from  the  stomach  by  washing,  and  its  precipitation,  wdiich  may  be 
best  accomplished  by  solutions  of  the  sulphates,  such  as  magnesium 
sulphate.  In  the  absence  of  the  sulphates,  white  of  egg  or  milk  is 
given. 

In  chronic  poisoning,  the  general  treatment  is  the  removal  of  the 
patient  from  the  danger  of  further  poisoning,  and  nutritious,  strength- 
ening diet.  The  iodide  of  potassium  has  been  said  to  accelerate  the 
elimination  of  lead  by  the  kidneys,  but  according  to  Lehmann's  experi- 
ments, is  not  superior  to  the  bromide  or  the  chloride  of  potassium,  and 
it  has  been  denied  recently  that  it  has  any  effect  on  the  excretion  by 
the  urine  or  by  the  intestine,  by  which  most  of  the  lead  escapes  from 
the  body.  In  practice,  however,  the  iodide  is  always  used.  Diuretics 
may  be  prescribed,  and  hot  baths;  sulphur  baths  are  especially  recom- 
mended, and  massage  is  said  to  hasten  the  elimination  of  the  poison. 

In  colic,  morphine  or  opium  is  often  necessary  to  allay  the  pain. 
Belladonna  or  atropine  is  used  less  frequently,  and  nitrite  of  amyl  is 
said  to  be  eflScient  for  a  short  time.  In  the  intervals  between  the 
paroxysms,  a  saline  cathartic  is  often  necessary  to  relieve  the  consti- 
pation, or  if  the  vomiting  prevents  this,  a  large  enema  may  be  thrown 
into  the  bowel. 
42 


658  THE  HEAVY  METALS 

In  arthralgia,  the  pain  may  necessitate  the  gi\ing  of  ()i)iates.  In 
anaesthesia  and  oncephaloi)athia,  the  treatment  is  exj)ectant  and  symp- 
tomatic; for  instance,  in  mania,  or  violent  delirium,  chloral  may  be 
necessary. 

In  paralysis,  strychnine  may  be  used  along  with  the  general  treat- 
ment, but  the  chief  reliance  is  to  be  placed  on  the  electrical  stimulation 
of  the  paralyzed  muscles,  first  with  the  galvanic  current,  and,  as  recovery 
sets  in,  with  the  induction  ^oil.  Massage  of  the  muscles  is  also  of 
benefit. 

Nephritis  and  gout  due  to  lead  poisoning  are  to  be  treated  in  the 
same  way  a»s  those  arising  from  other  causes. 

In  lead  works  and  paint  factories,  much  ma}'  be  done  to  prevent 
lead  poisoning  by  hygienic  measures  tending  to  lessen  the  inhalation 
of  dust,  and  the  contact  of  lead  with  the  food. 

When  symptoms  of  poisoning  have  appeared,  the  patient  ought  not 
to  be  allowed  to  work  again,  or  at  least  only  after  a  long  interval. 
Weak  and  anaeniic  men  ought  not  to  be  admitted  as  workmen,  and 
women  are  not  to  be  employed  in  lead  works  more  than  is  unavoidable. 

Bibliography. 

Hamack.     Arch.  f.  exp.  Path.  u.  Pharm.,  ix,  p.  152. 

Wyss.     Virchow's  Archiv,  xcii,  p.  193. 

Maier.     Ibid.,  xc,  p.  455. 

Annuschat.     Arch.  f.  exp.  Path.  u.  Pharm.,  vii,  p.  45;    x,  p.  261. 

Lehmann.     Zts.  f.  physiolog.  Chem.,  vi,  p.  528. 

Mann.     Brit.  Med.  Jour.,  1893,  i,  p.  401. 

Cash.     Schmiedeberg's  Festschrift,  p.  93. 

Oddo  et  Silbert.     Rev.  de  Med.,  1892,  p.  295. 

Riegel.     Deutseh.  Arch.  f.  klin.  Med.,  xxi,  p.  175. 

Borgen.     Ibid.,  Ivi,  p.  248. 

Ellenberger  u.  Hofmeister.     Arch.  f.  Thierheilkunde,  x,  p.  216. 

Westphal.     Archiv  f.  Psychiatric,  xix,  p.  620. 

Ceni.     Ibid.,  xxix,  p.  566. 

Luethje.     Ztschr.  f.  klin.  Med.,  xxix,  p.  266;    xxxi,  p.  112. 

Stood.     Arch.  f.  Ophthalmol.,  xxx,  iii,  p.  215. 

Schroeder.     Ibid.,  xxxi,  i,  p.  229. 

Cornil  et  Braull.     Journ.  de  I'Anat.,  1883,  p.  205. 

Coen  D'Ajutolo.     Ziegler's  Beitrage,  iii,  p.  451. 

Putnam.     Boston  Med.  and  Surg.  Jour.,  cxvii,  pp.  73,  596;   cxxviii,  p.  187. 

Ebstein.     Virchow's  Archiv,  cxxxiv,  p.  541. 

Eichhorsl.     Ibid.,  cxx,  p.  217. 

Lorimer.     Brit.  Med.  Jour.,  1886,  ii,  p.  163. 

Oliver.     Lancet,  1891,  ii,  p.  530.    Lead  poisoning,  London,  1891. 

While  and  Pepper.     Trans,  of  Amer.  Assoc,  of  Physicians,  1901,  p.  410. 

McCarthy.     Univ.  of  Pennsylvania  Med.  Bull.,  January,  1902. 

Billings.     Journ.  Amer.  Med.  Asso.,  1904,  p.  772. 

Legge  and  Goadby.     Lead  poisoning  and  lead  absorption,  London,  1912. 

Straub.     Seventeenth  Internat.  Cong,  of  Med.,  Section  V,  p.  61. 

liambousek.     Zeitschr.  f.  exp.  Path.  u.  Thcr.,  vii,  p.  1. 

V.    COPPER. 

Copper  seldom  gives  rise  to  poisoning,  and  is  much  less  frequently 
used  in  medicine  than  many  of  the  other  hea\y  metals.  The  soluble 
salts  ])rcci])itate  proteins  from  solution,  and  are  therefore  astringent 


COPPER  G59 

when  applied  to  the  iiiiicous  membranes  and  to  wounded  surfaces.  In 
Larger  quantities  they  are  somewhat  irritant  and  corrosive,  although 
much  less  so  than  mercury. 

Symptoms. — The  copper  salts  have  a  harsh,  metallic,  astringent  taste, 
and  when  swallowed  in  some  quantity  cause  nausea,  salivation,  and 
vomiting.  The  most  of  the  salt  is  thus  removed,  and  no  further  s\'mp- 
toms  are  observed.  Large  quantities,  however,  induce  corrosion  of  the 
walls  of  the  stomach  and  intestine,  and  give  rise  to  \iolent  vomiting 
and  purging,  the  copper  giving  a  blue  or  green  color  to  the  vomited 
matter  and  the  stools,  and  blood  appearing  in  them  later  from  the 
corrosion  of  the  mucous  membrane.  Violent  pain  in  the  abdomen  is 
complained  of,  and  the  usual  symptoms  of  acute  corrosive  poisoning 
may  follow — collapse,  with  weak  pulse  and  respiration,  headache 
giddiness,  unconsciousness,  delirium,  coma,  convulsions,  and  paralysis. 
These  may  prove  fatal  in  a  few  hours,  but  more  frequently  the  patient, 
lives  for  several  days  to  sink  eventually  from  exhaustion. 

The  nausea,  vomiting  and  purging  of  acute  copper  poisoning  are  due  to  the 
local  effect  on  the  mucous  membranes  of  the  stomach  and  intestine.  In  fact, 
although  some  copper  is  absorbed  in  these  cases,  there  is  no  reason  to  suppose 
tliat  any  of  the  acute  symptoms  are  due  to  it,  for  thej'  are  all  induced  bj^  other 
poisons  which  act  only  as  gastro-intestinal  irritants. 

The  occurrence  of  chronic  copper  poisoning  in  man  has  not  been  established. 
In  copper  and  brass  workers,  gastro-intestinal  catarrh,  or  colic  and  diarrhoea, 
occur  occasionally  and  are  ascribed  to  the  copper  swallowed  in  the  course  of 
their  occupation.  The  dust  inhaled  may  similarly  cause  larjaigeal  irritation 
and  bronchitis.  The  skin  and  hair  ha\-e  often  a  greenish  tint,  and  a  green  line 
on  the  teeth,  just  where  they  enter  the  gums,  is  kno\Mi  as  the  copper  line;  but 
it  is  believed  that  these  are  due  largely  to  the  copper  dust  deposited  on  the 
skin,  hair  and  teeth,  and  not  to  the  excretion  of  the  metal.  Local  paralysis, 
anaemia,  tremor,  emaciation  and  cutaneous  eruptions  are  said  to  have  followed 
these  sjTiiptoms  in  some  cases,  but  it  may  fairly  be  doubted  whether  these 
symptoms  are  really  due  to  the  copper  or  to  the  lead,  arsenic  and  other  poisons 
often  associated  with  it.  Furthermore,  copper  has  l3een  taken  in  the  form  of 
the  metal,  or  of  its  soluble  salts,  for  prolonged  periods  ^\dthout  any  symptoms 
being  elicited  except  those  of  slight  intestinal  catarrh  and  some  nausea.  Animals 
have  been  fed  with  food  containing  large  doses  of  copper  for  many  months, 
apparentl}^  without  any  sjonptoms  of  poisoning,  and  copper  is  found  so  regularly 
in  the  tissues  of  man  and  animals  that  it  may  be  regarded  as  a  normal  con- 
stituent, although  its  function  is  altogether  unknoAAii  and  it  may  be  merely 
stored  up  on  its  way  to  excretion. 

In  animals  the  general  action  may  be  ehcited  by  the  hijection  of  slowly  dis- 
sociated salts,  such  as  sodium-copper  tartrate  into  the  blood  or  subcutaneously. 
In  the  frog  copper  induces  great  weakness  and  eventually  complete  paralysis 
of  the  spontaneous  movements  and  of  the  heart.  This  appears  to  arise  from  a 
depressant  action  on  the  central  nervous  system,  but  the  muscles  are  also 
weakened  and  finally  completely  paralyzed;  often  fibrillary  contractions  are 
observed  eaxly  in  the  frog,  but  it  is  unknown  whether  these  are  of  central  or  of 
peripheral  origin.  The  heart  is  somewhat  accelerated  at  first  hj  very  small 
quantities,  but  later  becomes  slow  and  weak,  and  finally  ceases  in  diastole 
before  the  skeletal  muscles  are  paralyzed;  the  changes  in  the  heart  are  due  to 
direct  action  on  the  muscle. 

In  mammals  the  intravenous  injection  of  copper  does  not  cause  vomiting, 
but  the  locomotion  soon  becomes  slow,  clumsy  and  weak,  and  later  complete 
paralysis  of  the  spontaneous  movements  follows.     The  heart  and  respiration 


060  rilE  HEAVY  METALS 

seem  equally  invoh'cd,  but  the  respiration  ceases  somewhat  earlier  than  the 
heart.  The  blood-pressure  rises  slightly  after  the  intravenous  injection  of 
copper,  but  afterward  falls,  partly  on  account  of  the  weakness  of  the  heart, 
and  partly  from  dilatation  of  the  bloodvessels.  When  an  animal  survives 
longer,  violent,  sometimes  bloody,  diarrhoea  is  generally  induced  by  copper, 
as  by  most  of  the  other  heavy  metals.  The  animals  lose  flesh  rapidly,  and 
refuse  food,  and  the  urine  often  contains  all)umin,  and  according  to  some 
authoi's,  haemoglobin  and  blood.  In  the  rabbit  some  icterus  and  anaemia  is 
said  to  occur  from  the  destruction  of  the  red-blood  cells,  and  fatty  degeneration 
of  the  liver,  kidney  and  heart  has  been  observed.  Others  have  found  ecchy- 
moses  and  congestion  along  the  intestine  and  in  the  kidney  to  be  the  chief 
lesions.  Similar  results  are  obtained  in  rabbits  when  copper  is  given  by  the 
mouth,  as  this  animal  is  incapable  of  rejecting  the  poison  by  vomiting.  In  the 
ilog,  on  the  other  hand,  poisonous  doses  are  removed  bj^  vomiting  when  they 
are  given  by  the  mouth. 

Copper  is  absorbed  from  the  intestine,  for  large  quantities  have  been 
found  in  animals  fed  on  it  for  some  time;  a  large  proportion  of  the 
poison  is  absorbed  when  small  doses  are  given,  but  the  proportion 
lessens  as  the  dose  is  increased.  It  also  passes  into  the  blood  from  other 
mucous  surfaces  and  from  wounds.  It  is  said  to  have  a  strong  affinity 
for  haemoglobin  and  to  form  with  it  a  compound  which  Kobert  has 
named  cuprohtemol,  and  which  is  stated  to  be  formed  very  rapidly  when 
copper  is  injected  into  the  blood,  the  metal  leaving  the  serum  and 
attaching  itself  to  the  corpuscles  at  once.  The  copper  absorbed  from 
the  intestine  is  lodged  chiefly  in  the  liver,  less  in  the  spleen,  kidney,  and 
thyroid.  It  is  excreted  in  the  bile,  urine  and  saliva,  in  the  intestinal 
secretions,  and  in  traces  in  the  milk,  and  is  said  to  pass  from  the  mother 
to  the  foetus  in  utero.  Copper  is  found  in  small  quantities  in  these  organs 
and  secretions  in  man  and  in  animals  that  have  not  been  treated  ^^itll 
it,  but  in  much  larger  amount  after  prolonged  administration.  Taken 
by  the  mouth,  it  fails  to  cause  general  poisoning,  because  it  is  slowly 
absorbed,  and  also  because  what  is  absorbed  is  Avithdrawn  from  the 
blood  by  the  liver. 

Copi)cr  is  found  as  a  normal  constituent  of  the  blood  in  many  of  the  in\cr- 
tcbratcs,  in  which  it  performs  the  same  function  as  the  iron  of  tlu^  luTmoglobin 
in  the  vcrtel)rates.  It  has  been  detected  in  one  of  the  pigments  of  birds"  feathers, 
and,  as  has  been  stated,  is  so  frcciuently  found  in  the  tissues  of  mammals,  Ijolh 
wild  and  domesticated,  that  it  may  be  regarded  as  a  normal  constituent. 
Oysters  and  other  animals  take  it  up  in  large  quantities  when  they  live  in  water 
i-ich  in  copper,  and  apjjarently  are  not  injured  l)y  it.  Many  of  the  higher 
plants,  notal)ly  the  grajie  vine,  are  said  to  be  remarkal>ly  improved  by  the 
sprinkling  of  copper  on  their  leaves,  quite  apart  from  the  destruction  of  parasites; 
on  the  otiier  hand  it  does  not  promote  the  growth  of  cereals  in  any  way,  and 
it  is  a  deadly  poison  to  several  of  the  lower  plants.  Thus  traces  of  copper 
added  to  the  water  in  which  they  live,  destroy  some  of  the  simpler  algir,  and 
Naegeli  asserts  that  one  part  of  copper  in  one  thousand  million  parts  of  water  is 
sufficient  to  kill  these  plants.  The  parasites  of  the  grape  vine,  potato.  api)le 
and  other  i)lants  are  destroj'cd  ])y  spraying  the  i)lants  with  coi)i)er,  and  yeast 
cea.ses  growing  in  a  0.02  per  cent,  solution,  while  the  mouUls  seem  to  be  almost 
inunune  to  its  action.  Locke  found  that  the  traces  of  (•o})iier  contained  in 
water  distilled  in  copper  vessels  was  suflicient  to  destroy  tubifex  (one  of  the 
annelid  worms)  and  tadpoles,  while  BuchoUz  states  that  the  development  of 


COPPER  661 

bacteria  is  stopped  by  a  solution  of  copjier  sulphate  under  1  per  cent,  in  strength. 
Copper  thus  seems  to  have  a  ^•er^^  powerful  poisonous  action  on  certain  living 
forms  and  to  be  harmless  to  others,  and  the  subject  deserves  further  investiga- 
tion. It  is  possible  that  it  may  prove  to  act  prejudicially  to  some  human  para- 
sites, and  it  is  certainly  less  dangerous  to  man  than  many  other  remedies  used 
as  parasiticides  and  disinfectants. 

Cupri  Sulphas  (U.  S.  P.,  B.  P.)  (CUSO4+5H2O),  large,  transparent,  deep 
blue  crystals,  without  odor,  but  mth  a  nauseous,  metallic  taste,  soluble  in  water, 
scarcely  so  in  alcohol.    Dose  as  an  emetic,  0.25  G.  (4  grs.);  B.  P.,  5-10  grs. 

Therapeutic  Uses. — Copper  sulphate  is  used  internally  onlj'  as  an 
emetic,  and  for  this  purpose  ought  to  be  given  in  about  1  per  cent, 
solution.  It  acts  promptly,  and  does  not  leave  so  much  depression 
and  nausea  as  other  metallic  emetics,  and  for  this  reason  is  unsuitable 
as  an  expectorant.  In  phosphorus  poisoning  it  is  especially  valuable, 
as  in  addition  to  causing  e^'acuation  of  the  stomach,  the  metal  is  depos- 
ited on  the  particles  of  phosphorus  and  prevents  their  absorption. 

Externally  copper  sulphate  is  used  as  an  astringent  injection  in 
gonorrhoea,  and  occasionally  as  a  lotion  in  ulcers  and  wounds;  for  this 
purpose  it  is  employed  in  1  per  cent,  solution.  The  solid  crystals  are 
sometimes  used  to  touch  exuberant  granulations  for  their  astringent 
and  corrosive  effect. 

Small  quantities  of  copper  sulphate  have  recently  been  used  to 
destroy  the  algte  which  grow  in  reservoirs  and  often  give  the  water  a 
disagreeable  odor  and  taste.  The  proportion  of  copper  required  for  tliis 
purpose  is  about  one  part  in  a  million  or  sometimes  in  fifty  millions; 
this  treatment  does  not  render  the  water  deleterious  to  man,  for  much 
larger  quantities  of  copper  have  been  taken  constantly  without  injury. 
It  has  also  been  suggested  to  disinfect  water  contaminated  with  typhoid 
bacilli,  and  some  success  has  been  recorded,  though  these  organisms 
are  less  susceptible  to  copper  than  those  of  putrefaction;  the  pro- 
portion of  copper  required  for  this  purpose  appears  to  be  greater  than 
that  necessary  to  destroy  the  algse. 

The  chloride  of  copper  is  a  much  more  irritant  and  disinfectant  substance 
than  the  sulphate. 

In  cases  of  Poisoning  with  copper  salts,  the  stomach  generally  rejects  the 
metal  by  vomiting  and  no  emetic  is  required.  Non-corrosive  compounds  maj'^ 
be  formed  by  giving  milk,  egg,  or  other  forms  of  albumin,  tannic  acid,  mag- 
nesia, or  ferrocyanide  of  potassium.  ISIorphine  may  be  required  for  the  i)ain, 
ice  to  stop  the  vomiting. 

Bibliography. 

Harnack.     Arch.  f.  exp.  Path.  u.  Pharm.,  iii,  p.  44;    xvii,  p.  145. 

Lehmann.     Arch.  f.  Hygiene,  xxiv,  p.  1;    xxvii,  p.  1;    xxxi,  p.  279. 

Tschirch.  Das  Kupfer,  vom  Standpunkte  der  gericht.  Chemie,  Toxikologie  u.  Hygiene, 
Stuttgart,  1893. 

Schwartz.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxv,  p.  437. 

De  Moor.     Arch,  de  Pharmacodyn.,  i,  p.  81. 

Baum  u.  Seeliger.  Centralbl.  f.  Physiol.,  1896,  pp.  714,  752;  1897,  p.  797;  1898, 
p.  108. 

Locke.     Journ.  of  Phys.,  xviii,  p.  319. 

Ringer.     Ibid.,  xxii,  p.  xiv. 


CG2  THE  HEAVY  METALS 

Wolf.     Ztschr.  f.  physiolog.  Chcm.,  xxvi,  p.  442. 

Murray.     British  Med.  Journ.,  1900,  i,  p.  1334. 

Lewin.     Deutsch.  med.  Woch.,  1900.  p.  689. 

Richter.     Centralhl.  f.  Bacteriologic  (ii),  vii,  p.  417. 

Moore,  Kraemer.     Amer.  Journ.  of  Pharmacy,  1904,  pp.  553,  574. 

Yagi.     Arch,  internat.  de  Pharmacodyn.,  xx,  p.  51. 

VI.    ZINC. 

The  effects  of  zinc  resemble  those  of  copper  so  closely  that  they 
need  only  brief  mention.  Like  copper,  the  soluble  salts  precipitate 
proteins  and  therefore  possess  an  astringent  action,  or  in  large  quantities 
act  as  irritants  and  corrosives.  The  sulijhate  is  the  soluble  salt  most 
commonly  used  in  medicine,  but  the  chloride  has  frequently  given  rise 
to  corrosive  poisoning,  and  is  therefore  of  greater  importance  than  the 
chloride  of  copper.  The  sulphate  is  much  less  irritant  and  more  astrin- 
gent than  the  chloride,  wliich  is  used  only  as  a  caustic  and  disinfectant. 

Symptoms. — The  sidphate  of  zinc  has  a  harsh,  metallic  taste,  and  in 
small  doses  causes  nausea  and  vomiting,  in  larger  quantities  violent 
vomiting  and  purging,  pain  in  the  abdomen  and  collapse;  these  symp- 
toms are  due  to  the  local  action  on  the  stomach  and  intestme.  The 
insoluble  zinc  oxide  and  carbonate  are  less  liable  to  cause  acute  irrita- 
tion than  the  sidphate,  but  their  prolonged  ingestion  has  given  rise  to 
dyspepsia  and  constipation  or  diarrhoea  in  some  cases.  The  continued 
administration  of  zinc  salts  has  no  effects  in  man,  except  those  of 
disordered  digestion  and  constipation,  and  Lehmann  could  detect  no 
effects  in  the  dog  after  the  administration  of  155  G.  of  the  carbonate 
in  the  course  of  335  days,  although  a  considerable  amount  of  the  metal 
had  been  absorbed. 

in  workers  exposed  to  zinc  fumes  a  condition  known  as  brassfounders' 
ague  is  occasionally  met  with.  It  is  ushered  in  by  dryness  of  the  throat, 
hard  cough,  metallic  taste,  constriction  of  the  chest,  lassitude  and 
weakness,  sometimes  with  nausea  and  vomiting;  muscle  cramps  and 
joint  pains  are  often  present,  and  later  prolonged  rigors  and  sliivering 
are  followed  by  a  rapid  acceleration  of  the  pulse,  coughing  and  soreness 
of  the  chest,  and  headache.  These  symptoms  give  place  to  profuse 
perspiration,  and  the  patient  sinks  into  a  sleep  from  which  he  awakes 
in  ordinary  health.  The  attack  has  been  attributed  to  the  absorption 
of  decomposition  products  of  the  proteins  destroyed  by  the  fumes  of 
zinc  inhaled;  it  is  held  that  the  same  symptoms  would  arise  from  the 
fumes  of  other  metals,  but  these  are  less  volatile  than  zinc  and  ar(> 
therefore  seldom  inhaled.  A  number  of  obscure  nervous  conditions 
have  also  been  described  as  arising  from  zinc  in  workmen  in  brass 
factories  and  bronze  works,  but  it  is  questionable  whether  they  arc 
really  due  to  the  zinc  or  to  its  impurities,  such  as  arsenic  and  lead. 

Action.— Tlio  <j;('Iht:i1  action  of  ziiio  can  1)C  observed  only  when  a  double 
salt,  is  injected  iiitra\'enously  or  liypodennieally.  as  the  ordinary  sails  pre- 
cii)itate  the  proteins  of  the  blood  when  injected  into  a  vein,  and  cause  acute 
irritation  when  applied  subcutaneously.     In  the  frog,  zinc  is  found  to  cause 


ZINC  G63 

weakness  and  lessened  reflex  excitability,  and  the  heart  becomes  weak  and 
inefficient,  irregular  and  slow,  and  eventually  ceases  in  diastole;  the  voluntary 
muscles  respond  more  weakly  to  the  electric  current  in  life  and  lose  their  irrita- 
bility entirely  soon  after  death. 

In  mammals,  the  intravenous  injection  of  zinc  causes  vomiting  and  diarrhoea, 
weakness,  tremor  and  paralysis  of  the  extremities;  and  the  stomach,  intestines 
and  heart  contain  small  haemorrhages.  The  blood-pressure  seems  to  be  but 
little  affected,  until  just  before  death,  but  the  pulse  is  slowed.  Helpup  found 
that  the  subcutaneous  injection  of  zinc  salts  induced  congestion  and  parenchy- 
matous inflammation  of  the  kidney. 

Zinc  seems  therefore  to  depress  the  central  nervous  system  and  to  a  less 
extent  the  heart  and  voluntary  muscles,  and  to  cause  irritation  and  congestion 
of  the  mucous  membrane  of  the  stomach  and  intestine  and  inflainmation  of 
the  kidney.  The  fact  that  vomiting  occurs  from  the  intravenous  injection  of 
zinc  salts  is  explained  by  the  metal  inducing  inflammation  in  the  stomach. 

Lehmann  found  that  of  the  zinc  absorbed  from  the  stomach  and  intestine, 
most  is  contained  m  the  liver  and  bile,  less  in  the  spleen,  kidney,  thyroid  and 
pancreas,  and  very  little  in  the  other  tissues.  Zinc  is  excreted  by  the  stomach 
and  intestinal  waUs,  and  in  much  smaUer  amounts  in  the  bile  and  urine. 

Locke  found  zinc  to  possess  a  poisonous  action  on  the  tadpole  and  tubifex 
when  present  in  traces  in  the  water  in  which  they  lived,  but  this  effect  was 
weaker  than  that  of  copper.  Richter  states  that  zinc  is  less  poisonous  to  fungi 
than  copper,  and  very  weak  solutions  seem  to  promote  their  growth.  The 
zinc  salts  seem  to  be  in  general  much  weaker  than  those  of  copper,  whicli  they 
resemble  closely  in  other  respects. 

Preparations. 

ZiNCi  Sulphas  (U.  S.  P.,  B.  P.)  (ZnS04  +  THaO),  colorless,  transparent, 
odorless  crystals,  with  a  harsh,  astringent,  metallic  taste,  soluble  in  water, 
not  in  alcohol.    1.0  G.  (15  grs.);  B.  P.,  10-30  grs. 

Ziiici  Oxidum  (U.  S.  P.,  B.  P.)  (^nO),  an  amorphous  white  powder  without 
odor  or  taste,  insoluble  in  water.    0.25  G.  (4  grs.);  B.  P.,  3-10  grs. 

Zinci  Carbonas  Prcecipitatus  (U.  S.  P.),  Zinci  Carbonas^  (B.  P.),  a  preparation 
varying  somewhat  in  composition,  but  always  containing  some  oxide,  which 
it  resembles  in  appearance  and  solubility. 

Unguentum  Zinci  Oxidi  (U.  S.  P.),  20  per  cent. 

Unguentum  Zinci  (B.  P.),  15  per  cent,  of  the  oxide. 

Zinci  Chloridum  (U.  S.  P.,  B.  P.)  (ZnCb),  a  white  powder,  or  porcelain-like 
mass,  irregular  or  moulded  into  pencils,  odorless  and  strongly  caustic,  very 
deliquescent  and  soluble  in  water  and  alcohol. 

Liquor  Zinci  Chloridi  (U.  S.  P.,  B.  P.),  50  per  cent. 

Zinci  Phenolsulphonas  (U.  S.  P.)  (Zn(C6H604S)2  +  8H2O),  colorless  crystals 
with  an  astringent  taste,  soluble  in  water  and  in  alcohol.  Used  externally  in 
1  per  cent,  solution. 

Therapeutic  Uses. — Zinc  sulphate  has  been  used  internally  as  an 
emetic,  but  not  so  widely  as  the  sulphate  of  copper,  although  it  is 
equally  efficient.  The  sulphate,  the  oxide  and  the  carbonate  have  been 
advised  in  the  treatment  of  various  brain  diseases,  from  the  erroneous 
belief  that  zinc  is  a  sedative.  The  oxide  and  sulphate  are  seldom 
employed  as  astringents  in  diarrhoea. 

Externally  the  zinc  preparations,  with  the  exception  of  the  chloride, 
are  used  as  astringents,  the  sulphate  being  applied  in  solution,  the 
oxide  and  carbonate  as  powders  or  ointments.  The  oxide  is  especially 
useful  as  an  application  in  many  skin  diseases.    Solutions  of  the  sulphate 


f 


G04  THE  HEAVY   METALS 

are  used  as  an  eye  wash  (one-half  per  cent.)  and  as  an  injection  in  gonor- 
rhcea  (1-4  per  cent.)-  In  the  last  case  it  is  sometimes  formed  into  a 
mixture  with  acetate  of  lead,  the  sulphate  of  lead  which  results  being 
credited  with  some  astringent  action  and  not  being  washed  off  so 
readily  from  the  diseased  surface.  The  phenolsulphonate  is  also  used  as 
a  urethral  injection,  and  the  salicylate  and  the  sulpho-iodolate  of  zinc 
have  also  been  introduced  as  astringent  and  antiseptic  applications. 

The  chloride  of  zinc  differs  from  the  other  salts  in  being  a  powerful  caustic, 
and  is  ii.st'd  as  a  paste  or  in  pencil  form  to  destroy  malignant  growths,  or  in 
chancH's  and  gangrenous  sores.  It  jn-oduces  a  white  eschar  and  is  said  to  he 
less  hable  to  Hi)i'ead  over  the  surface  than  jiotash,  but  penetrates  the  ei)iderniis 
with  difficulty,  and  it  is  therefore  advisable;  to  destroy  tliis  with  potash  or  a 
l)listcr  l)efore  applying  the  caustic.  It  is  sometimes  mixed  witli  flour  or  dried 
gypsum  and  water  to  a  paste  (Canquoin's  paste),  when  a  less  active  caustic 
is  desired.  Its  use  is  much  more  restricted  at  the  prtisent  time  than  former!}'. 
Burnett's  disinfecting  solution  (a  somewhat  stronger  solution  than  the  official 
liquor)  is  used  to  disinfect  hvcen  and  urinals,  and  the  liquor  of  the  i)harma- 
copceia  may  be  employed  for  the  same  i)urpose.  It  has  freciucntly  given  rise 
to  severe  corrosive  poisoning  from  being  swallowed  accidentally  or  suicidally. 

The  acetate,  bromide,  iodide  and  valei-ianate  have  exactly  the  same  effect 
as  the  sulphate  and  are  quite  superfluous.  Poisoning  witli  zinc  is  treated  in 
the  same  way  as  that  with  copper. 

Bibliography. 

Harnack.     Arch.  f.  exp.  Path.  ii.  Pharm.,  iii,  p.  53. 

BuchoUz.     Ibid.,  iv,  p.  64. 

Ilelpup.     Inaug.  Diss.,  Greifswald,  1889;  Deutsch.  med.  Woch.,  1889,  p.  782. 

Hacher.     Arbeit,  a.  d.  pharmak.  Instit.  zu  Doipat,  ix,  p.  88. 

Lehmann.     Arch.  f.  Hygiene,  xxviii,  p.  291;    Ixxii,  p.  358. 

Morner.     Ibid.,  xxxiii,  p.  160. 

Jacohy.     Arb.  a.  d.  k.  Gesundheitsamte,  xv,  p.  204. 

VOlcker.     Beitrilgo  z.  klin.  Chirurg.,  xxvii,  p.  592. 

Kichter.     Centralbl.  f.  Bacteriologie  (ii),  vii,  p.  417. 

Sigel.     Viertcljalirschr.  f.  gericlit.  Med.,  xxxii,  p.  174. 

Hayhursl.     Amer.  Journ.  Med.  Sciences,  cxlv,  p.  723. 

Kisskalt.     Zeitschr.  f.  Hygiene,  Ixxi,  p.  472. 

Vn.    SILVER. 

The  only  salt  of  silver  used  at  all  extensively  in  medicine  is  the 
nitrate,  which  is  caustic,  astringent,  and  disinfectant.  Added  to  solu- 
tions, of  jjroteins,  it  forms  a  heavy  precipitate,  wliich  is  at  first  wliite 
in  color,  but  turns  darker  in  the  light  as  the  silver  is  reduced. 

Symptoms. — In  dilute  solution  silver  is  a  slight  irritant  to  the  skin, 
and  causes  redness  and  itching  only,  but  more  concentrated  solutions 
blister,  and  the  s(jlid  nitrate  of  siher  causes  an  eschar,  which  is  at  first 
white,  but  later  turns  black  from  the  reduction  of  the  silver  in  light. 
On  the  mucous  membranes,  dilute  solutions  act  as  astringents,  but  con- 
centrated cause  irritation  and  corrosion.  The  caustic  action  of  siher 
does  iu)t  extend  so  dee])ly  as  that  of  some  other  metals,  such  as  mer- 
cury, because  the  penetration  of  the  metal  is  limited  by  the  formation 
of  the  insoluble  chloride.  On  the  other  liaud,  tlu>  silver  salts  are  more 
itriliiiit  than  those  of  lead. 


SILVER  GG5 

The  astringent  action  is  due  to  the  formation  of  a  protective  layer  of 
coagulated  albumin.  If  irritation  is  induced  the  vessels  are  dilated,  and 
there  is  no  evidence  that  they  are  ever  contracted  in  the  practical  use 
of  silver. 

In  acute  silver  poisoning  from  the  ingestion  of  silver  nitrate,  the 
symptoms  are  those  of  severe  gastro-intestinal  irritation  and  corrosion. 
Burning  pain  is  felt  in  the  throat  and  abdomen,  and  is  followed  by 
nausea  and  vomiting  and  often  by  purging.  The  mouth  is  covered 
with  a  grayish-white  membrane,  wliich  turns  darker  after  a  time,  but 
this  is  absent  if  the  poison  be  swallowed  in  the  solid  form,  as  has  hap- 
pened sometimes.  The  corrosion  of  the  stomach  and  intestine  cause 
collapse,  with  weak  pulse,  shallow  respiration  and  pinched  features  and 
this  may  be  followed  by  coma,  convulsions,  and  death.  The  throat, 
stomach  and  intestine  presented  the  ordinary  appearances  of  acute 
corrosive  poisoning  in  one  case  in  which  an  autopsy  was  performed. 

Action.- — The  symptoms  of  acute  poisoning  are  due  to  the  local  action,  and 
present  no  features  suggesting  that  silver  is  absorbed  and  causes  general  poison- 
ing. The  action  of  silver  after  absorption  has,  however,  been  investigated 
in  animals  poisoned  by  subcutaneous  or  intravenous  injection.  The  nitrate, 
owing  to  its  coagulating  properties,  is  unsuitable  for  this  purpose,  and  the 
hj^posulphite  of  sodium  and  silver,  or  a  solution  of  the  albuminate  has  therefore 
been  used.  In  mammals  the  central  nervous  system  is  the  chief  seat  of  action, 
especiall}^  the  medulla  oblongata,  which  seems  to  be  stimulated  at  first,  for  the 
blood-pressure  rises  and  the  pulse  is  somewhat  slow,  owing  to  increased  activity 
of  the  vasomotor  and  vagus  centres.  Later  the  blood-pressure  falls  and  the 
respiration  becomes  slow  and  labored,  and  eventually  ceases  from  paralysis 
of  the  centre.  Gaethgens  asserts  that  the  diaplu-agm,  and  eventually  the  other 
striated  muscles  are  paralyzed  soon  afterward.  The  heart  is  comparatively 
little  affected  and  often  continues  to  beat  some  time  after  the  respiration  has 
stopped.  In  less  acute  poisoning,  when  the  animal  survives  the  injection  for 
several  hours  or  days,  a  marked  increase  in  the  broncliial  secretion,  culminating 
in  oedema  of  the  lungs,  has  been  noted;  no  satisfactorj^  explanation  of  this  has 
been  advanced,  but  it  does  not  seem  due  to  cardiac  inefficiencj^  and  occurs  also 
when  the  excised  lung  is  perfused  with  blood  containing  silver.  Congestion 
and  ecchymoses  are  found  in  the  stomach  and  intestine,  and  some  authors 
mention  ulceration  of  these  mucous  membranes.  Cohnstein  found  that  small 
quantities  of  silver  salts  injected  intravenously  cause  some  increase  in  the 
urine  for  a  time,  but  that  larger  quantities  are  followed  by  albuminuria. 

In  cold-blooded  animals  and  in  invertebrates,  silver  preparations  are  said 
to  cause  violent  convulsions,  resembUng  those  of  strychnine  and  followed  by 
general  paral3'sis. 

The  general  action  of  silver  is  thus  apparently  directed  first  of  all  against 
the  medulla  oblongata,  the  rest  of  the  central  nervous  sj^stem  being  affected 
to  a  less  extent.  The  mucous  membrane  of  the  stomach  and  intestine  is  acted 
on,  as  by  most  heavy  metals,  and  the  kidney  is  also  Hable  to  irritation.  CEdema 
of  the  lungs  occurs  frequently. 

Chronic  Poisoning. — There  is  no  evidence  that  in  acute  poisoning  in 
man  any  considerable  amount  of  the  metal  is  absorbed  from  the  stomach 
and  intestine.  When  silver  is  given  for  prolonged  periods,  however, 
some  is  absorbed,  although  probably  only  a  minute  fraction  of  that 
actually  swallowed.  None  of  it  is  found  in  the  epithelium  of  the  stomach 
and  intestine,  and  some  of  it  may  circulate  in  the  blood  in  a  soluble  form 


666  THE  HEAVY   METALS 

for  a  short  time.  But  the  greater  proportion  is  very  soon  thrown  down 
in  tlie  form  of  minute  granules,  which  were  formerly  believed  to  be 
metallic  silver,  but  which  have  more  recently  been  said  to  be  one  of  its 
organic  compounds.  The  formation  of  this  pigment  is  quite  different 
from  the  reduction  of  silver  in  sunlight,  for  it  occurs  in  complete  dark- 
ness. The  change  apparently  takes  ])lace  in  the  cells,  especially  in  the 
leucocytes,  but  the  granules  are  afterward  extruded  into  the  surround- 
ing fluid.  They  are  found  in  the  connective  tissues  of  the  body  chiefly, 
and  when  present  in  quantity,  give  a  dark  color  to  the  skin  and  mucous 
membranes.  This  pigmentation  (Argyria)  was  much  commoner  formerly, 
when  the  nitrate  was  used  in  the  treatment  of  epilepsy.  jNIore  recently 
it  has  occurred  in  the  makers  of  artificial  pearls,  who  use  siher  as  a 
])igment. 

Local  argyria  is  sometimes  met  with  from  the  prolonged  application 
of  silver  nitrate  to  the  eye  or  throat,  when  it  tints  the  eyelids  and  mouth, 
and  from  working  with  silver,  when  the  hands  are  permanently  black- 
ened from  the  granules  being  forced  into  the  skin. 

The  deposit  of  the  silver  in  the  skin  gives  it  a  darker  color,  varying 
from  light  gray  in  mild  cases  to  a  darker  slate  shade  after  more  pro- 
longed use.  It  is  generally  distributed  all  over  the  body,  but  in  some 
cases  has  been  especially  marked  in  the  face,  and  it  is  said  to  begin 
in  the  gums,  where  it  causes  a  dark,  slate-colored  line  somewhat  re- 
sembling the  lead  line.  In  the  skin  it  is  found  in  the  corium,  not  in 
the  epidermis.  The  deposit  and  the  dark  color  extend  throughout 
the  alimentary  canal  and  the  respiratory  passages,  the  granules  occur- 
ring in  the  connective  tissue,  particularly  in  the  intestinal  villi,  and 
not  in  the  epithelimn.  The  glomeruli  of  the  kidneys,  the  connective 
tissue  of  the  liver  and  spleen,  the  choroid  plexus,  the  timica  intima 
of  the  aorta,  the  serous  membranes,  and  the  mesenteric  lymph  glands 
contain  more  of  the  deposit  than  other  organs.  The  pigmentation  is 
not  accompanied  by  any  other  symptoms  of  importance,  and  the 
victims  li^•e  to  old  age  without  suiTering  from  the  chronic  poisoning  in 
any  way,  except  from  the  annoyance  induced  by  the  change  in  color. 

Argyria  is  quite  incurable,  although  many  attempts  have  been 
made  to  remove  it.  Iodide  has  been  tried,  for  the  most  part  without 
effect,  and  blistering  is  equally  valueless,  as  the  pigment  lies  deeper 
than  the  epidermis.  The  only  known  solvent  of  the  granules  is  cyanide 
of  potassium,  and  of  course  this  is  inadmissible,  owing  to  its  powerfid 
poisonous  action. 

Argyria  has  been  induced  in  animals  by  prolonged  treatment  with 
small  doses  of  silver  salts,  though  here  the  pigment  is  not  found  in  the 
skin,  but  in  the  duodenal  mucous  membrane  and  the  mesentery  attached 
to  it,  the  mesenteric  lyrnj)!!  glands,  the  spleen,  and  liver.  A  deposit 
of  silver  i)igment  has  also  been  induced  in  animals  by  a  single  injection 
of  a  non-irritant  preparation  into  a  vein,  or  into  the  subcutaneous 
tissue.  Here  the  silver  is  found  at  first  in  the  liver  capillaries,  the 
glomeruli  of  the  kidney,  the  intestine  and  the  bone  marrow,  but  is 
afterward  taken  up  by  the  leucocytes,  and  carried  to  all  the  organs  of 
tlie  b()d\-. 


SILVER  GG7 

In  man  it  seems  likely  that  most  of  the  silver  passes  through  the 
alimentary  canal  unabsorbed  and  that  the  small  proportion  taken  up 
by  the  tissues  is  precipitated  and  remains  embedded  in  them  indefi- 
nitely, for  the  pigmentation  remains  unchanging  in  its  depth,  and  there 
is  therefore  no  reason  to  suppose  that  any  of  the  silver  is  eliminated. 

In  animals,  however,  some  of  the  silver  injected  h}T)odermically  or 
intravenously  is  excreted  by  the  epithelium  of  the  alimentary  canal. 
Xone  appears  in  the  urine.  In  the  frog  silver  injected  hypodermically 
is  all  excreted  by  the  epithelium  of  the  tongue,  is  swallowed,  and  passes 
out  in  the  foeces.  Xo  other  poison  is  known  to  be  eliminated  by  this 
channel. 

Silver  nitrate  is  a  powerful  antiseptic,  partly  from  its  action  in 
coagulating  the  proteins  of  the  microorganisms,  partly  from  the  specific 
effects  of  the  metal. 

Preparations. 

Argenti  Nitras  (U.  S,  P.,  B.  P.)  (AgNOa),  colorless  crystals  which  become 
gray  or  grayish-black  on  exposure  to  light  in  the  presence  of  organic  matter, 
with  a  bitter,  caustic,  stronglv  metallic  taste,  verv  soluble  in  water,  less  so 
in  alcohol.    0.01  G.  (|  gr.);  B.  P.,  i-^  gr. 

Argenti  Nitras  Fusus  (U.  S.  P.),  moulded  nitrate  of  silver,  lunar  caustic 
— a  white,  hard  solid,  generally  cast  in  the  form  of  pencils. 

Argexti  Nitras  Induratus  (B.  P.),  toughened  caustic,  silver  nitrate  fused 
with  5  per  cent,  of  nitrate  of  potassium. 

The  sih'er  preparations  ought  to  be  kept  in  dark  amber-colored  bottles,  in 
order  to  prevent  their  being  reduced  bj'  light,  and  ought  not  to  be  prescribed 
with  organic  matter,  which  rapidly  reduces  them. 

Therapeutic  Uses. — Silver  nitrate  pills  have  been  recommended  in 
some  forms  of  dyspepsia  and  vomiting,  and  in  gastric  ulcer,  and  have 
also  been  used  as  astringents  in  diarrhoea,  but  generally  with  little 
benefit.  A  very  ancient  use  of  silver  oxide  and  more  recently  of  the 
nitrate,  is  that  in  the  treatment  of  epilepsy,  chorea,  tabes  and  various 
other  nervous  diseases.  This  dates  from  the  Arabs,  and  is  said  to 
have  originated  from  the  astrological  medicine  of  that  period,  which 
taught  that  nervous  diseases  were  especially  affected  by  the  phases  of 
the  moon,  which  was  associated  with  silver  in  their  system  (hence 
lunar  caustic,  lunacy).  Clinical  experience  shows  that  silver  is  of  no 
benefit  in  epilepsy,  and,  in  fact,  it  is  improbable  that  silver  reaches 
the  central  nervous  system  in  any  other  form  than  inert  granules. 
This  use  of  silver  very  often  gave  rise  to  argyria  without  benefiting 
the  patient,  about  15-30  G.  proving  sufficient  to  cause  marked  pig- 
mentation. 

Externally  silver  nitrate  is  employed  very  extensively,  the  sticks  of 
lunar  caustic  being  used  to  destroy  warts  and  other  small  skin  growths, 
to  arrest  capillary  htemorrhage,  to  destroy  the  false  membranes  of 
diphtheria  and  for  other  similar  purposes.  A  solution  of  2-5  per  cent, 
may  also  be  applied  to  cauterize  chancres  and  indolent  ulcers,  and  one 
of  1-2  per  cent,  may  be  painted  on  mucous  membranes  as  an  irritant 
disinfectant;  a  solution  of  common  salt  is  then  used  to  wash  the  part, 


GG8  THE  HEAVY  METALS 

in  order  to  remove  the  excess  of  silver.  In  ophthalmia,  especially  of  the 
infectious  form,  a  solution  of  1-2  per  cent,  is  extremely  valuable,  and, 
in  fact,  a  routine  treatment  in  some  lying-in  hospitals  is  to  wash  the 
eyes  of  the  infant  with  this  solution  immediately  after  birth  as  a  pro- 
phylactic measure  to  prevent  ophthalmia,  k  solution  of  this  strength 
is  only  to  be  used  by  the  surgeon  himself,  and  the  eye  should  be  washed 
out  with  a  salt  solution  at  once.  A  more  dilute  solution  (one-fourth  to 
one-half  per  cent.)  may  be  used  as  a  lotion  for  the  eye  more  frequently, 
may  be  applied  to  extensive  denuded  surfaces,  as  burns,  and  is  often 
thrown  into  the  rectum  in  chronic  dysentery.  In  gonorrha'a,  the 
nitrate  of  silver,  1  part  in  500-2,000  of  water,  is  used  as  an  injection, 
and  is  found  to  have  great  value,  destroying  the  gonococci  and  promoting 
healing.  Very  much  stronger  solutions  (up  to  5  per  cent.)  have  been 
used  to  abort  the  disease  in  its  onset,  but  cause  great  pain. 

The  precipitation  of  silver  nitrate  by  proteins  and  chlorides  confines  its 
disinfectant  action  to  narrower  limits  than  those  of  some  other  bactericides, 
and  this  has  led  to  the  introduction  of  a  number  of  other  compounds,  whicli 
are  less  easily  dissociated  and  accordingly  less  liable  to  be  thrown  out  of  solu- 
tion. Thus  argodamine,  a  10  per  cent,  solution  of  silver  phosjihate  in  10  ])er 
cent,  ethylendiamine  solution,  has  been  used,  in  gonorrha?a  diluted  to  1: 1,000- 
5,000,  in  "the  eye  in  5  per  cent,  solution.  It  penetrates  better  than  silver  nitrate, 
but  the  alkaline  diamine  renders  it  somewhat  irritating.  Another  recent  product 
is  argonin,  which  is  a  combination  of  casein  and  silver,  is  soluble  in  water,  and, 
like  argentamine,  is  not  precipitated  by  chlorides  nor  by  albumin;  it  is  a  some- 
what weaker  disinfectant  than  the  nitrate  and  argentamine.  The  lactate  of 
silver,  adol,  and  the  citrate,  ilroV,  have  also  been  used  as  disinfectants.  Actol 
is  soluble  in  water  and  resembles  the  nitrate  in  coagulating  proteids,  while 
itrol,  on  the  other  hand,  is  practically  insoluble  (1  to  3,800  water).  The  former 
is  used  in  solution  (?,  per  cent.),  the  latter  as  a  disinfecting  powder  in  wounds. 
Actol  and  argonin  have  been  shown  to  have  very  considerable  disinfectant 
power  in  test-tube  cultures,  and  actol  lessens  the  putrefaction  in  the  bowel 
and  constipates  to  some  extent,  but  argonin  has  no  effect  on  the  intestinal 
microbes.  Prulargol,  largin,  argyrol  and  many  other  compounds  of  silver  have 
been  introduced,  but  the  best  known  in  the  last  few  years  has  been  Crede's 
colloid  silver  {Collargol),  which  is  metallic  silver  in  colloid  form,  which  may  be 
suspended  in  water  (4  per  cent.)  or  in  ointment  (10-15  per  cent.).  This  has  been 
advertised  as  a  bactericide  in  the  most  diverse  conditions,  and  has  been  injected 
hypodcrmically,  and  even  intravenously,  to  destroy  microbes  in  the  tissues. 
But  it  has  no  disinfectant  action,  and  in  fact  is  a  very  inert  body,  which  is  de^•oid 
of  any  therapeutic  i)roperties.  It  may  be  added  that  none  of  these  newei' 
preparations  are  superior  to  the  nitrate  in  efficiency  as  disinfectants,  and  thost' 
that  are  less  irritant  are  also  less  reliable. 

Silver  i)rei)arations  ought  not  to  be  used  for  long  jieriods,  as  argyria  has 
been  induced  in  three  months  and  after  the  use  of  15-30  G.  (|-1  oz.)  of  the 
nitrate. 

In  cases  of  poisoning  with  silver  nitrate,  eggs,  milk  and,  al)ove  all,  conuuon 
salt  solution  are  indicated  to  form  ins()lul)le  comiHnuuls.  In  argyria  no  iniiJiove- 
nient  can  be  expected,  though  the  iodide  of  potassium  may  be  tried. 

Bibliography. 

Bogoslowshj.     Virchow's  Ardiiv,  xlvi,  p.  409. 
Jacoby.     Arch.  f.  exp.  Path.  u.  Plianii.,  viii,  p.  108. 
Rozsahegzi.     Ibid.,  ix,  p.  289. 


BISMUTH  ()G9 


Locw.     Pfliiger's  Arcliiv,  xxxiv,  pp.  596,  602. 

Schubert.     Zts.  f.  Heilkimde,  xvi,  p.  341. 

Samojloff.     Arb.  a.  d.  pharm.  Instit.  Dorpat,  ix,  p.  27. 

Gerschun.     Ibid.,  x,  p.  154. 

Tschisch.     Virchow's  Archiv,  c,  p.  147. 

Crede.     Arch.  f.  klin.  Chiiurg.,  Iv,  p.  861. 

Mosse.     Zts.  f.  phys.  Chem.,  xxiii,  p.  160. 

Marshall  and  Ncave.     Brit.  Med.  Journ.,  1906,  Aug.  18. 

Van  dcr  Does.     Zts.  f.  phys.  Chem.,  xxiv,  p.  351. 

Atlianasiu.     Journ.  de  Physiol.,  iii,  p.  163. 

Bial.     Ztschr.  f.  physikal.  Chem.,  xl,  p.  513. 


VIII.    BISMUTH. 


The  insoluble  salts  of  bismuth,  in  especial  the  subnitrate,  have  long 
enjoyed  a  reputation  in  the  treatment  of  gastric  and  intestinal  irrita- 
tion, and  have  more  recently  been  advised  in  surgery  as  applications 
to  granulating  wounds. 

Symptoms. — Taken  in  therapeutic  doses,  the  subnitrate  induces  no 
marked  symptoms,  even  after  prolonged  use.  It  has  little  or  no  taste, 
and  passes  through  the  stomach  and  intestine  for  the  most  part  unab- 
sorbed.  It  does  not  seem  to  affect  the  passage  of  food  through  the 
stomach  in  most  cases,  but  is  believed  to  lessen  the  secretion  of  acid 
under  some  conditions.  In  the  intestine  it  is  said  to  have  some  effect 
in  increasing  the  leucocytes  of  the  blood,  and  often  causes  some  con- 
stipation. It  gives  the  stools  a  black  color,  which  is  generally  believed 
to  be  due  to  the  formation  of  the  sulphide  of  bismuth,  but  which  Quincke 
ascribes  to  the  reduction  of  the  subnitrate  in  the  intestine. 

Very  little  of  the  bismuth  swallowed  is  absorbed,  but  several  author- 
ities have  found  traces  in  the  urine  of  patients  treated  with  it  inter- 
nally, so  that  some  evidently  passes  into  the  blood  under  certain 
unknown  conditions.  Enormous  quantities  have  been  administered 
internally  without  any  symptoms  of  poisoning  being  elicited,  but  in 
one  or  two  cases  some  stomatitis  has  been  remarked,  while  in  other 
instances  large  concretions  of  bismuth  have  been  found  in  the  stomach 
and  bowel. ^  Some  of  the  older  writers  describe  serious  poisoning 
from  bismuth,  but  this  was  not  due  to  the  drug  itself,  but  to  the  lead, 
arsenic,  or  antimony  with  which  it  was  contaminated.^  Since  its  use 
was  extended  to  wounded  surfaces,  several  cases  of  serious  intoxication 
have  occurred.  The  symptoms  are  salivation,  swelling  of  the  gums, 
tongue  and  throat,  pain  and  difficulty  in  swallowing,  black  spots  in 
the  mouth  and  throat,  and  gangrene  of  the  soft  palate  and  other  parts 
of  the  mucous  membrane  of  the  mouth.  Vomiting,  diarrhoea  and 
albuminuria  follow,  but  the  patients  generally  recover  when  the  dress- 

'  Large  quantities  of  bismuth  subnitrate  have  been  given  by  the  mouth  or  rectum  in 
Rontgen-ray  examination  of  the  stomach  and  bowel,  and  in  a  few  cases  fatal  poisoning 
has  occurred  from  nitrites  being  formed  from  the  nitrate  and  leading  to  the  formation 
of  methsemoglobin  in  the  blood  cells.  This  danger  may  be  avoided  by  using  the  carbonate 
instead  of  the  subnitrate. 

2  A  symptom  formerly  noted  in  cases  treated  with  bismuth  was  an  extremely  disagree- 
able odor  in  the  breath,  but  this  has  been  shown  to  be  due  to  the  presence  of  tellurium  in 
the  preparation. 


G70  THE  HEAVY  METALS 

\\\^  is  removed  from  the  wound.  In  these  cases  much  k'ss  hismuth 
is  ai)i)Hed  tiiaii  is  often  prescribed  for  internal  use,  so  that  it  would 
ai)]5ear  that  it  is  absorbed  more  rai)idly  from  o;ranulatinfi:  surfaces 
than  from  the  mucous  membranes,  or  that  what  is  absorbed  from 
the  stomach  and  intestine  is  prevented  by  the  liver  from  reaching  the 
general  circulation. 

Action. — Tlie  general  action  of  bismuth  has  been  studied  in  animals  Ijy  tlie 
sulicutaneous  or  intravenous  injection  of  the  double  salts,  such  as  the  tartrate 
of  bismuth  and  sodium.  In  frogs  the  symptoms  are  those  of  stimulation  of 
the  spinal  cord  and  mechiUa  oblongata,  followed  b}^  depression  and  paralysis. 

In  mammals  also  large  doses  act  chiefly  on  the  central  nervous  system.  The 
respiration  is  accelerated,  the  heart  slowed,  and  violent  clonic;  and  tonic  con- 
\-ulslons  follow  at  short  intervals,  during  which  the  movements  arc  weak  and 
incoordmated.  Toward  the  fatal  issue  of  the  injection  the  heart  often  ceases 
entirely  for  some  time  and  then  regains  its  former  rhythm  quite  suddenly. 
The  blood-pressure  falls,  partly  owing  to  the  weakness  of  the  heart,  partly 
from  depression  of  the  vasomotor  centre. 

Smaller  quantities  injected  intravenously  or  subcutaneously  into  mammals 
induce  a  more  chronic  form  of  intoxication,  which  resembles  that  seen  in  man. 
The  earliest  symptoms  are  loss  of  appetite,  vomiting  and  diarrha'a,  salivation 
and  stomatitis  with  ulceration  of  the  gums,  tongue,  and  buccal  mucous  mem- 
brane. Weakness,  slowness  and  incoordination  of  the  movements  follow,  and 
except  in  very  few  chronic  cases,  tetanic  convulsions  occur  at  intervals.  The 
urine  contains  albumin  and  casts.  The  weakness  gradually  deepens  into  com- 
plete paralysis  and  the  animal  dies,  generally  without  convulsions.  The  heart 
seems  little  affected  in  the  chronic  intoxication,  but  the  blood-pressure  is  low 
from  the  intestinal  irritation  and  general  collapse. 

Besides  the  stomatitis  and  ulceration  of  the  mouth,  the  post-mortem  appear- 
ances in  chronic  bismuth  poisoning  in  animals  consist  in  some  congestion, 
inflammation  and  necrosis  in  the  kidney,  and  an  intense  black  coloration  of 
the  cajcum  and  the  upper  part  of  the  large  intestine.  This  pigmentation  is 
limited  very  exactly  by  the  ileocecal  valve,  and  extends  throughout  the  thick- 
ness of  the  bowel  wall.  The  mucous  membrane  may  also  be  necrosed  in  places 
and  ulcers  and  haemorrhages  arc  met  with  in  it.  The  black  coloration  is  due 
to  a  deposit  of  bismuth  sulphide  on  the  mucous  membrane  and  in  the  capillary 
vessels  and  b^mph  spaces.  Meyer  and  Steinfeld  found  that  bisnuith  is  excreted 
all  along  the  alimentary  canal,  but  in  larger  quantities  in  the  caecum  and  large 
intestine  than  elsewhere,  and  they  ascribe  the  ulceration  to  the  precijiitation 
of  the  sulphide  in  the  vessels  and  the  consequent  arrest  of  the  blood  ciu'rent. 
When  sulphide  solution  was  artificially  introdu('(>d  into  the  stomach  and  small 
intestine,  bisnuith  caused  necrosis  and  ulceration  here  also,  so  that  there  is 
considerable  support  for  this  view. 

They  found  bismuth  to  be  stored  in  considerable  quantity  in  the  li\'er  and 
to  be  excreted  by  the  urine,  stomach  and  intestine,  but  especially  by  the  cax'um 
and  large  bowel.  It  has  been  found  in  the  saliva  by  other  obser\ers,  and  perhaj^s 
in  traces  in  the  milk,  although  the  last  is  not  satisfactorily  establislicd. 

The  action  of  bismuth  in  acute  poisoning  in  animal  exj-jeriments  seemfe  there- 
fore to  be  exerted  on  the  medulla  and  spinal  cord,  to  a  less  extent  on  the  heart, 
while  in  chronic  intoxication  the  organs  affected  are  those  by  which  it  is  excreted 
— the  mouth,  kidney,  large  intestine,  and  c£Ecum. 

Preparations. 

BiSMUTHi  SuBNiTRAs  (U.  8.  P.,  ii.  P.),  whitc  bismuth,  Magisterium  Bis- 
muthi,  bisnuith  oxynitrate,  a  iieavy,  white,  insoluble  powder,  odorless  and 
almost  tasteless,  with  a  slight  acid  reaction.     It  consists  of  a  mixture  of  the 


BISMUTH  671 

hydrate  and  subnitratc  of  hismuih  in  varying  proportions.  0.5  G.  (7|  grs.); 
B.  P.,  5-20  gXH.,  in  powder  or  suspendrd  in  water. 

Bismulhi  Suhcarbonos  (U.  S.  P.),  Bisnndhi  Carhonas  (B.  P.),  l)isnuith  oxy- 
earbonatc,  a  white  or  pale  yellowish-white  powder,  varying  in  composition, 
odorless,  tasteless,  insoluble  in  water  or  alcohol.     Dose  as  for  subnitrale. 

Trochiscus  Bismxdhi  Composihis  (B.  P.);  each  contains  2  grs.  of  bismuth 
oxy carbonate  along  with  the  carbonates  of  magnesia  and  lime 

Bismulhi  Snlicylas  (B.  P.),  Bismuthi  Subsaliajlas  (U.  S.  P.)  the  salicylate, 
or  oxysalicylate,  of  bismuth  is  a  white,  amorphous  powder,  insoluble  in  water. 
0.25  G.  (4  grs.);  B.  P.,  5-20  grs. 

The  citrate  and  suhgallotc  of  bismuth  have  been  suggested  in  doses  of  2-4  grs. 
(0.12-0.25  G.)  but  have  no  advantages  over  the  better  known  salts;  the  only 
soluble  preparation  which  has  been  introduced  is  the  double  citrate  of  bismidh 
and  ammonmm  (2  grs.). 

Therapeutic  Uses. — Bismuth  has  been  used  chiefly  in  gastric  catarrh 
and  ulcer,  and  has  often  been  looked  upon  as  a  specific  in  the  last 
affection,  though  it  acts  simply  as  a  protective  powder  with  perhaps 
some  astringent  properties.  It  has  been  found  that  when  swallowed 
it  is  at  first  deposited  in  the  most  dependent  part  of  the  stomach,  but 
is  later  distributed  evenly  over  the  surface  and  forms  a  continuous 
sheet  over  any  ulceration,  which  it  thus  protects  from  mechanical 
injury  from  the  food,  and  also  from  the  chemical  action  of  the  gastric 
juice.  The  subnitrate  is  the  only  one  of  the  official  preparations  largely 
used  for  this  purpose,  and  is  generally  administered  in  quantities  of 
2-3  G.  (30-45  grs.)  per  day  in  powder.  Recently  the  use  of  much 
larger  quantities  (10-15  G.,  150-250  grs.,  per  day)  has  been  recom- 
mended. Bismuth  has  also  been  used  in  diarrhoea  for  its  astringent  and 
protective  action  on  the  intestine,  which  is  again  due  to  its  being 
deposited  on  the  mucous  membrane  and  acting  as  a  mechanical  coating 
over  irritated  siu-faces.  If  bismuth  is  prescribed  with  alkalies,  the  car- 
bonate should  be  used,  as  the  subnitrate  is  slightly  acid  in  reaction. 

The  subnitrate  has  been  advised  in  surgery  as  an  antiseptic,  astrin- 
gent powder  to  replace  iodoform.  It  is  true  that  it  is  devoid  of  the 
disagreeable  odor  of  the  latter,  but  it  is  not  a  harmless  remedy,  as  was 
at  first  supposed,  for  several  cases  of  bismuth  poisoning  have  been 
recorded  from  its  surgical  use.  Like  iodoform,  its  value  depends  not 
so  much  on  its  germicidal  action  as  on  its  absorption  of  the  fluids  of 
the  wound,  which  renders  the  surface  less  suitable  for  the  growth  of 
bacteria.  The  therapeutic  uses  of  the  bismuth  preparations  then  are 
largely  due  to  their  insolubility.  The  subnitrate  is  generally  used, 
the  carbonate  less  frequently,  while  the  soluble  double  citrate  is  quite 
superfluous. 

Several  new  compounds  of  bismuth  have  been  introduced  in  therapeutics 
of  late  years,  chiefly  with  the  intention  of  combining  the  astringent  properties 
of  bismuth  with  the  antiseptic  action  of  benzol  preparations.  Among  these 
may  be  mentioned  the  salicTjlate  and  benzoatc,  which  have  been  used  as 
intestinal  antiseptics  and  astringents.  Others  are  airol  (bismuth  oxyiodide 
gallate),  thioform  (bismuth  dithio-salicylate)  bismuth  phenolate,  cresolate,  orphol 
C^-naphtolate),  xeroforyn  (tribromphenolate),  tannatc,  sulphocarbolate,  dermol 
(chrysophanate),  eudoxin  (tetraiodophenolphtaleinate) .    These  have  been  used 


(;72  THIC  HEAVY  METALS 

chiefly  as  cutaneous  applications  in  various  forms  of  skin  disease,  in  wliich 
an  astring;ent  and  protective  powder  is  indicated,  in  burns  and  ulcers,  in  some 
ophthalmic  conditions  and  as  dusting  powders  after  operations. 

Bibliography. 

Meyer  u.  Steinfcld.     Arch.  f.  cxp.  Path.  u.  Pharm.,  xx,  p.  40. 
DalchS  el  Villcjean.     Arch.  gen.  do  Med.,  1887,  ii,  p.  129. 
Jasenski.     Arch,  des  Sciences  biolog.,  ii,  p.  247. 
Surveyor  and  Harley.     Brit.  Med.  Jour.,  1895,  ii,  p.  1483. 
Kocher.     Volkmann's  Klinische  Vortrage,  No.  224. 

K.    ALUMINIUM  AND  ALUM. 

The  chief  pharmacopoeial  preparation  of  aluminium  is  the  sulphate 
of  aluminium  and  potassium,  or  alum,  which  has  been  largely  used 
for  its  astringent  properties.  Alum  solutions  precipitate  proteins 
in  the  same  way  as  the  salts  of  the  other  heavy  metals,  and  dilute 
solutions  have  thus  an  astringent  action,  while  larger  quantities  and 
more  concentrated  solutions  act  as  irritants.  This  is  more  especially 
the  case  when  dried  alum  is  applied,  for,  in  addition  to  its  coagulating 
effect  on  the  proteins,  this  preparation  has  a  great  avidity  for  water. 

Symptoms. — Alum  solutions  have  a  sweetish,  astringent  taste,  and 
in  small  quantities  induce  no  symptoms  except  a  feeling  of  dryness 
and  astringency  of  the  mouth  and  throat,  and  some  constipation. 
Larger  doses  act  as  gastric  irritants  and  cause  nausea  and  vomiting, 
and,  in  extreme  cases,  purging.  Even  the  largest  quantities,  however, 
are  followed  by  no  symptoms  except  those  of  gastro-intestinal  irritation 
and  inflammation,  and  the  long-continued  use  of  alum  does  not  elicit 
any  symptoms  of  chronic  poisoning.  The  aluminium  salts  are  only 
absorbed  in  syiall  quantity  from  the  stomach  and  intestine,  so  that  no 
symptoms  of  general  poisoning  arise  from  the  internal  use  of  the  salt. 
Aluminium  vessels  may  be  used  for  cooking,  or  even  to  contain  acids, 
without  danger  of  intoxication,  as  has  been  shown  by  a  recent  series  of 
investigations.  The  small  amount  of  aluminium  absorbed  is  stored 
up  in  the  liver,  kidney,  muscles  and  pancreas  and  slowly  excreted  in 
the  bile  and  urine. 

Aluminium  salts,  especially  the  acetate,  chloride  and  some  more 
recent  preparations,  have  very  considerable  antiseptic  i)ower,  much 
more  than  some  of  the  more  generally  used  antiseptics,  such  as  boric 
acid. 

Action. — Aluminium  has  a  very  remarkable  general  action  when  it  ol)tains 
access  to  the  l)lood.  In  Siem's  experiments  on  animals,  the  sodium-aluminium 
lactate  or  tartrate  induced  a  very  slow  intoxication,  mammals  never  dying 
from  the  effects  sooner  than  one  or  two  weeks  after  the  intra^•enous  injection 
of  the  salts.  In  frogs  the  symptoms  were  those  of  a  descending  paralysis  of 
the  central  nervous  system,  the  heart  and  the  peripheral  nerves  and  muscles 
being  little  affected.  In  mannnals  the  first  symptoms  appeared  ()nly  after 
three  to  five  days,  and  consisted  in  constipation,  rapid  loss  of  weight,  weak- 
ness, torpor  an(i  vomiting;  marked  abnormalities  in  movement  and  sensation 
were  oljserved  later,  such  as  tremor,  jerking  movements,  clonic  convulsions, 


ALUMINIUM  AND  ALUM  673 

paresis  of  tlic  hind  legs,  aiursthcsia  of  the  moutli  and  throat,  and  lessened 
sensation  all  over  the  bod.y.  Before  death,  diarrheea  often  set  in,  and  albu- 
minuria was  generally  present.  The  mucous  membrane  of  the  stomach  and 
bowel  was  found  swollen  and  congested,  the  kidney  and  liver  had  often  under- 
gone fatty  degeneration,  and  haemorrhages  were  found  in  the  renal  cortex. 
Aluminium  was  found  in  the  urine. 

Like  the  other  members  of  the  heavy  metal  series,  aluminium  therefore 
acts  on  the  bowel  and  kidney  in  general  poisoning,  while  many  of  the  sjaiip- 
toms  point  to  a  direct  action  on  the  brain.  Dollken  has  recently  confirmed 
Siem's  results  and  showed  that  the  nerve  cells  and  fibres  of  the  cord  and  medulla 
undergo  degeneration,  particularly  those  of  the  lower  cranial  nerves. 

A  metal  which  is  very  nearly  related  to  ahnninium  in  its  effects  in  the  organism 
is  Beryllium.  It  differs  chiefly  in  being  more  poisonous,  in  being  absorbed 
from  the  stomach  and  intestine,  and  in  causing  more  distinct  lesions  in  these 
when  it  is  injected  into  the  blood. 

Preparations. 

Alumen  (U.  S.  p.,  B.  p.),  alum,  potassium^  alum,  (A1K(S04)2+12H20),  large, 
colorless,  octahedral  crystals,  with  a  sweetish,  strongly  astringent  taste,  soluble 
in  water,  but  not  in  alcohol.    0.5  G.  (7|  grs.);  B.  P.,  5-15  grs. 

Ghjcerinum  Aluminis  (B.  P.),  10  per  cent. 

Alumen  Exsiccatum  (U.  S.  P.,  B.  P.),  burnt  alum,  dried  alum  (A1K(S04)2), 
a  white,  granular  powder,  attracting  moisture  on  exposure  to  air,  soluble  in 
water. 

Alumini  Hydroxidum  (U.  S.  P.)  (A1(0H)3),  a  white,  light,  amorphous 
powder,  odorless,  tasteless,  insoluble  in  water  or  alcohol,  but  soluble  in  hydro- 
chloric or  sulphuric  acid  and  in  fixed  alkalies. 

Uses. — -Alum  is  used  chiefly  externally  for  its  astringent  properties. 
It  has  been  emploj^ed  as  an  emetic,  but  is  less  reliable  than  the  sul- 
phate of  copper  or  tartar  emetic,  and  very  large  doses  (4-8  G.,  1-2 
drs.)  are  required.  In  diarrhoea  either  alum  or  the  hydrate  is  some- 
times advised. 

Alum  solution  is  useful  as  an  astringent  gargle  (1-5  per  cent.),  as 
an  injection  in  gonorrhoea  (^-l  per  cent.),  as  an  astringent  lotion  in 
skin  diseases  (1  per  cent.),  and  for  other  similar  purposes.  Dried 
alum  is  more  caustic,  from  its  withdrawing  fluid  from  the  tissues;  it 
has  been  used  as  an  application  to  exuberant  granulations,  haemorrhoids, 
or  condylomata,  and  as  a  styptic  in  bleeding  from  the  nose  or  teeth. 
A  solution  (1  per  cent.)  has  been  injected  into  the  rectum  in  chronic 
dysentery,  but  is  inferior  to  the  nitrate  of  silver. 

A  large  nimiber  of  aluminium  preparations  have  been  introduced  recently 
as  antiseptic  astringents.  Among  these  may  be  mentioned  alumnnl  (naphtol 
sulphonate  of  aluminium),  salumin  (salicylate),  tannal  (tannate),  gallol  (gallate), 
horal  (borotartrate) ,  cutol  (borotamiate),  ahol  (acetate),  alkasal  (salicylate  of 
potassium  and  aluminium.  They  are  used  partly  in  solution,  chiefly  as  dusting 
powders. 

Bibliography. 

Siem.     Inaug.  Diss.,  Dorpat.,  1886. 

Dollken.     Arch.  f.  exp.  Path.  u.  Pharm.,  xl,  p.  98. 

Jalan  de  la  Croix.     Ibid.,  xiii,  p.  210. 

Plagge  u.  Lebbin.     Ueber  Feldflaschen  und  Kochgeschirre  aus  Aluminum,  Berlin,  1893. 

'  The  B.  P.  also  admits  ammonium  instead  of  potassium. 
43 


G74  THE  HEAVY  metals 

X.     MINOR  METALS. 

Gold. 

Gold  has  never  been  largely  used  in  therapeutics,  although  repeated  attempts 
have  been  made  to  introduce  it  in  the  treatment  of  the  most  diverse  conditions; 
the  salt  employed  has  almost  invariably  been  the  double  chloride  of  gold  and 
sodium.  It  is" much  less  poisonous  than  many  of  the  other  metals,  and  may 
be  taken  for  many  months  without  entailing  any  untoward  sjanptoms.  The 
subcutaneous  injection  in  frogs  is  followed  by  paralysis  of  the  central  nervous 
system,  gold  possessing  little  action  on  the  heart  and  striated  muscles  in  these 
animals.  Injected  intravenously  in  dogs,  it  causes  vomiting  and  dyspncra, 
which  soon  jmss  off,  but  if  sufficient  has  been  injected  the  animal  suffers  from 
nausea,  vomiting  and  diarrhoea  for  several  days,  eats  nothing,  loses  flesh  rapidly, 
and  dies  a  week  or  more  after  the  experiment.  Numerous  ulcers  are  found 
in  the  stomach  and  intestine,  and  these  often  betray  their  presence  in  life  by 
haMuorrhages.  Gold  lowers  the  blood-pressure  somewhat  on  intravenous  in- 
jection, probably  from  the  dilatation  of  the  mesenteric  vessels  accompanying 
the  intestinal  action.  It  has  little  eftect  on  the  rate  of  the  heart  except  in  large 
doses,  and  dilates  the  vessels  when  perfused  through  them.  When  given  by 
the  mouth  to  dogs  and  cats,  it  is  at  once  ejected  from  the  stomach  by  vomiting. 

Gold  has  therefore  the  ordinary  general  effects  of  the  heavy  metals  in  causing 
acute  irritation  and  ulceration  of  the  alimentary  canal.  The  vomiting,  diarrhcea 
and  ulceration  of  the  stomach  and  intestine  probably  indicate  that  it  is  excreted 
b}^  these  organs. 

Gold  has  been  used  in  various  nervous  disorders,  in  particular  in  those  of  a 
hysterical  nature,  and  may  conceivably  be  of  value  through  suggestion,  if  the 
patient  be  informed  of  the  nature  of  the  remedy.  Of  late  years  it  has  been 
widely  aclvertised  as  a  specific  in  chronic  alcoholism,  but  analysis  has  shown 
that  no  gold  was  contained  in  the  fluid  advocated,  and  there  is  no  reason  to 
suppose  that  it  is  of  value  except  by  means  of  suggestion. 

Bibliography. 

Aronoivilsch.     Inaug.  Dissertation,  Wurzburg,  1881. 
Schultz.     Inaug.  Dissertation,  Dorpat,  1892. 

Platinum. 

Platinum  resembles  gold  in  its  ac^tion  very  closely,  but  is  much  more  jioisonous. 
In  the  frog  it  i)aralyzes  the  central  nervous  system  and  later  the  striated  nuisdes. 
Kebler  observinl  a  stage  of  convulsions  precede  that  of  i)aralysis,  the  sjxisms 
evidently  arising  from  the  spinal  cord  or  medulla  oblongata.  In  nuunmals  the 
symptoms  resemble  those  of  gold  poisoning  in  almost  every  detail.  Small  quan- 
tities of  platinum  double  salts  injected  intravenously  increase  the  urine  to 
some  extent;  larger  injections  cause  albuminuria. 

Platinum,  like  gold,  was  at  one  time  advised  in  syphilis,  but  has  never  been 
widely  used. 

BlBLIOGR.\PHY. 

Kebler.     Arch.  f.  exp.  Path.  u.  Pharm.,  ix,  p.  137. 
Cohnstein.     Ibid.,  xxx,  p.  127. 

Chromium. 

Chromium  is  used  in  medicine  in  the  form  of  chromic  acid  and  the  bichro- 
mate of  potas.sium,  which  are  both  powerful  oxidizing  bodies  in  addition  to 


MINOR  METALS  ()75 

tlieir  i)i)i,S()iious  action  as  inotallic  oxides.  Tho  former  property  renders  them 
more  irritant  and  corrosive  than  most  of  the  salts  of  the  heavy  metals.  Chromic 
acid  in  particnlar  is  a  powerful  caustic,  combining  the  action  of  a  metallic 
oxide,  an  acid  and  a  strongly  oxidizing  agent.  Applied  to  the  skin  in  substance 
it  corrodes  it,  but  is  said  to  cause  less  pain  than  the  more  penetrating  caustic 
potash.  Even  in  dilute  solution,  the  chromic  salts  and  the  acid  act  as  skin 
irritants,  and  the  caustic  effects  are  sho\\Ti  by  skin  diseases,  and  particularly 
b}''  deep,  perforating  ulcers  in  persons  exposed  constantl}^  to  the  dust  of  chromic 
salts  in  factories.  These  ulcers  arise  from  anj-  abrasion  of  the  skin,  and  the 
cartilaginous  septum  of  the  nose  is  also  a  common  seat  of  ulceration,  which 
eventually  leads  to  perforation.  Thej^  are  due  to  the  local  action  of  the  poison 
and  not  to  its  absorption;  thej'  are  said  to  be  almost  painless.  The  inhalation 
of  the  dust  leads  to  chronic  bronchitis,  while  that  swallowed  and  absorbed  may 
give  rise  to  nephritis. 

Symptoms. — In  acute  poisoning,  wdien  a  large  quantity  of  the  acid  or  of  a 
salt  is  swallowed,  the  sjniiptoms  are  those  of  gastro-intestinal  corrosion,  intense 
pain  in  the  throat  and  stomach,  vomiting  and  purging,  wath  blood  in  the  vomited 
matter  and  the  stools,  collapse,  and  frequently  death.  The  mouth  and  throat 
are  stained  j-ellow,  and  the  stomach  and  intestine  exhibit  the  usual  appearance 
of  violent  corrosive  poisoning. 

The  general  action  of  chromic  preparations  may  be  elicited  in  animals  by 
subcutaneous  or  intravenous  injection,  or  by  the  administration  of  smaller 
ciuantities  by  the  mouth.  The  sjTuptoms  resemble  those  caused  by  the  general 
action  of  other  metals.  In  the  frog  increasing  weakness,  tremor,  and  eventually 
paralysis  of  the  central  nervous  system  are  induced.  In  the  mammal  weakness 
and  slo^^'nessin  the  movements  is  follow^ed  by  albuminuria,  glj-'cosuria,  diarrhoea, 
and  vomiting.  Sometimes  twitching  of  the  muscles  or  even  convulsions  are 
seen,  and  then  the  weakness  passes  into  general  paralysis.  The  heart  seems 
little  affected  bj^  chromium,  but  the  blood-pressure  falls.  After  death  the 
stomach  and  bowel  are  found  congested,  and  the  mucous  membrane  is  necrosed 
and  ulcerated  in  some  parts,  covered  wdth  ecchjinoses  in  others.  Haemorrhages 
are  also  found  in  other  organs  of  the  body,  notably  in  the  heart  wall.  The  kidney 
is  in  a  state  of  acute  parenchymatous  nephritis  and  may  contain  deposits  of 
uric  acid;  albumin,  casts,  and  often  blood  cells  appear  in  the  urine.  In  chronic 
poisoning  interstitial  nephritis  is  said  to  occur. 

Chromic  acid  and  its  salts  are  readily  absorbed  from  the  stomach  and  intestine. 
The}'  seem  to  be  excreted  for  the  most  part  through  the  kidney,  to  a  less  extent 
bj'  the  intestinal  epithehum  p^obablJ^  In  the  urine  the  metal  occurs  in  part 
in  organic  combination. 

Preparations. 

Aciduvi  Chromicum  (B.  P.),  Chromii  Trioxidum  (U.  S.  P.),  chromic  acid 
or  anhydride  (CrOs),  forms  crystals  of  dark  purplish-red  color  and  metallic 
lustre,  odorless,  verj^  soluble  in  water.  When  brought  in  contact  with  organic 
substances^  such  as  alcohol,  glycerin  or  sugar,  it  oxidizes  them  rapidly  and 
often  violently  with  explosion. 

Potassii  Bichromas  (B.  P.),  Potassii  Dichromas  (U.  S.  P.),  biclu'omate  or 
dichromate  of  potassium  (K2Cr207),  forms  large,  orange-red  transparent  crystals, 
with  a  bitter  metallic  taste,  soluble  m  ten  parts  of  water.    10  mgs.  (1  gr.). 

Chromic  acid  is  used  as  a  caustic  application  to  malignant  growths,  chancres 
and  diphtheritic  membranes,  to  a  less  extent  as  an  irritant  antiseptic.  It  has 
generally  been  applied  by  dipping  a  glass  rod  into  a  solution  formed  by  allowing 
the  crystals  to  deliquesce,  or  it  may  be  fused  on  the  end  of  a  wire.  It  has  also 
been  advised  in  5  per  cent,  solution  as  an  application  to  prevent  perspiration 
of  the  feet  and  to  harden  the  skin. 


G7G  THE  HEAVY  METALS 


Bibliography. 

Priestley.     Jour,  of  An.at.  and  Phys.,  xi.,  p.  285. 

Gergcns.     Arch.  f.  exp.  Path.  u.  Pharm.,  vi,  p.  148. 

Pander.     Kol)ert's  Arb.  a.  d.  pharm.  Instit.  zu  Dorpat,  ii,  p.  1. 

Hermanni.     Miinch.  med.  Wochcnschr.,  1901,  i,  p.  53G. 

Kossa.     Pfliiger's  Archiv,  Ixxxviii,  p.  627. 

Manganese. 

Traces  of  manganese  are  found  in  the  blood  and  tissues  of  man  and  animals 
very  frequently,  but  this  metal  is  not  an  essential  constituent  of  the  body,  but 
is  apparently  absorbed  accidentally  with  the  food.  The  salts  of  manganese 
in  large  quantities  cause  acute  irritation  of  the  stomach  and  intestine,  like 
those  of  the  other  hea\^^  metals,  and  a  form  of  chronic  poisoning  has  been 
described  in  workmen  exposed  to  manganese  dust;  the  symptoms  are  chiefly 
hysterical  laughter  or  grief,  and  similar  psychical  manifestations,  and  later 
motor  disturbances  which  are  chiefly  exhibited  in  a  spastic  gait  and  increased 
tendon  reflexes.  Manganese  is  absorbed  from  the  alimentary  tract  only  in 
very  small  quantity,  and  it  appears  to  resemble  iron  closely  in  its  course  through 
the  tissues.  Its  general  action  has  been  elicited  by  the  hypodermic  or  intravenous 
injection  of  double  salts.  In  frogs  manganese  injected  hypodermically  causes  a 
descending  paratysis  of  the  brain  and  spinal  cord,  and  later  weakens  and  arrests 
the  heart,  while  the  peripheral  muscles  and  nerves  seem  unaffected.  In  mammals 
large  injections  induce  epileptiform  con\'ulsions,  particularly  in  the  rabbit  and 
guinea-pig.  Smaller  quantities,  which  cause  a  less  acute  intoxication,  induce 
in  the  dog  nausea  and  vomiting,  diarrhoea,  weakness,  somnolence,  stupor,  and 
death  from  arrest  of  the  respiration.  The  urine  is  often  increased,  and  contains 
bile  pigment,  and,  toward  death,  albumin  and  casts.  The  stomach  and  bowel 
present  no  congestion  or  ulceration  in  these  cases.  Manganese  is  found  in  the 
vomited  matter  and  the  stools,  in  the  Uver,  kidney  and  intestinal  wall,  to  a  less 
extent  in  the  other  organs.  In  acute  poisoning  in  mammals  the  blood-pressure 
falls,  from  depression  and  paralysis  of  the  vasomotor  centre,  while  the  heart  is 
affected  only  much  later.  In  subacute  poisoning  the  darker  color  of  the  urine 
indicates  icterus,  but  this  is  much  more  marked  when  small  quantities  are 
repeatedly  injected  into  the  subcutaneous  tissues,  and  chronic  poisoning 
induced.  In  chronic  cases  the  nephritis,  which  is  showni  in  the  acute  poison- 
ing by  albuminuria,  is  also  more  developed,  the  inflammation  commencing  in 
the  secretory  cells  of  the  kidney  but  later  involving  the  interstitial  tissue,  if  the 
animal  lives  long  enough. 

Manganese  injected  hypodermically  or  subcutancously  is  excreted  chiefly  by 
the  intestinal  epithelium,  to  a  less  extent  by  the  kidney. 

Manganese  has  been  advised  in  chlorosis  and  especially  in  amenorrhcoa, 
in  which  it  is  l)elieved  by  many  to  have  a  specific  action,  while  others  have 
found  it  of  no  value  in  cither  of  these  conditions.  In  amenorrha\i  the  per- 
manganate of  potassium  is  generally  prescribed,  but  it  is  at  once  reduced  in 
the  stomach  to  the  dioxide. 

Bibliography. 

Harnack.     Arch.  f.  exp.  Path.  u.  Pharm.,  iii,  p.  58;    xlvi,  p.  372. 

Kobert.     Ibid.,  xvi,  p.  361. 

Cahn.     Ibid.,  xviii,  p.  129. 

Stockman.     Brit.  Med.  Jour.,  1893,  i,  p.  942. 

Embden.     Deutsch.  med.  Woch.,  1901,  p.  795. 

Jaksch.     Journ.  Amer.  Med.  Asso.,  1913,  ii,  p.  1042. 

Cadmium  i(>seinbles  zinc  very  closely  in  its  effects. 

Nickel  and  Cobalt  .salts,  adniinistered  to  the  frog,  cause  a  curious  dark  color 
in  the  skin,  followed  by  convulsive  inovcnients,  which  at  first  arise  apparently 


i 


MINOR  METALS  G77 

from  the  medulla  oblongata  and  liigher  centres,  and  resemble  those  of  picrotoxin, 
but  later  are  reflex,  froni  excessive  irritability  of  the  spinal  cord.  In  mammals 
the  usual  s\'mptoms  arising  from  the  action  on  the  intestine  and  kidney  are 
accompanied  by  tremors  and  chorea-like  movements,  later  by  tetanus,  and 
finallj'  by  paralj'sis.  These  metals  also  cause  a  profound  fall  in  blood-pressure 
resemljling  that  from  arsenic  and  apparently  arismg  from  direct  action  on  the 
walls  of  the  arterioles  and  capillaries.  Stronglj^  acid  food  may  form  nickel  salts 
when  it  is  cooked  in  vessels  made  of  this  metal,  but  no  poisoning  results,  either 
because  the  quantity  ingested  is  too  small  or  because  it  is  too  slowly  absorbed 
from  the  stomach  and  intestine.  Cobalt  nitrate  has  been  recommended  as  an 
antidote  in  prussic  acid  poisoning,  as  it  forms  an  insoluble  cyanide,  but  appears 
to  be  of  little  or  no  value;  the  oxide  has  been  applied  externally  as  an  astringent 
antiseptic  powder. 

Tin  salts  paralyze  the  central  nervous  system  in  the  frog,  and  later  the  heart. 
In  mammals  diarrhoea,  colic,  vomiting  and  general  weakness  are  observed, 
along  with  paralysis  of  some  parts  of  the  central  nervous  system  and  stimulation 
of  others,  leading  to  ataxia,  stiffness  and  irregularity  of  the  movements,  and 
occasionally  con^allsions.  The  sulphide  is  said  to  be  deposited  in  the  lymph 
spaces  of  the  intestines  in  the  same  way  as  in  bismuth  poisoning.  General 
poisoning  maj^  be  induced  by  the  administration  of  the  salts  by  the  mouth, 
eA'en  when  there  is  no  corrosion  of  the  mucous  membrane.  Tin  is  often  contained 
in  preserved  foods  containing  acids,  from  being  dissolved  off  the  vessels,  and  is 
certainly  absorbed,  for  it  has  been  detected  in  the  urine  after  the  use  of  such 
articles.  Apparenth'  it  is  not  often  present  in  sufficient  quantities  to  induce 
poisoning,  for  although  some  cases  of  "tin  poisoning"  are  met  with  in  medical 
literature,  in  none  of  them  has  it  been  satisfactorily  estabhshed  that  tin  was 
the  cause.  Clu'onic  poisoning  from  this  cause  is  unlvno^\^l,  and  animals  present 
no  symptoms  from  prolonged  treatment  with  larger  quantities  of  tin  than  are 
contained  in  any  preserved  foods. 

Thallium  salts  seem  to  resemble  those  of  lead  in  their  effects,  but  have  a 
powerful  depressant  action  on  the  heart,  and  are  said  to  be  more  poisonous. 
Richet  states  that  the  injection  of  thallium  acetate  in  animals  is  followed  bj^  a 
general  atrophy  of  the  muscles,  especially'  of  those  of  the  jaw  and  spme,  while 
its  continued  use  has  caused  falhng  of  the  hair  in  man  and  animals. 

Vanadium  is  said  to  mduce  sjanptoms  in  workmen  in  various  industries  in 
which  it  is  used.  These  consist  m  diarrhoea  followed  by  severe  constipation, 
ansemia,  emaciation  and  some  indefinite  nervous  disturbances;  albumin,  casts, 
and  blood  often  appear  in  the  urme.  Haemorrhage  from  the  lungs  is  not 
infrequent  and  lesions  are  found  in  the  lungs,  kidneys,  fiver,  and  intestinal 
tract.  The  symptoms  observed  in  acute  poisoning  in  animals  resemble  those 
mduced  by  the  other  irritant  metalfic  poisons.  Jackson  states  that  the  intra- 
venous injection  of  the  vanadates  m  animals  causes  a  sharp  rise  in  the  arterial 
pressure  from  constriction  of  the  peripheral  vessels;  this  arises  from  an  action 
on  the  muscle  wall  of  the  arterioles  for  the  most  part,  though  the  myoneural 
junctions  may  also  be  involved.  The  intestinal  walls  and  the  bronchioles  are 
similarly  aroused  to  contraction  by  vanadates. 

Molybdenum  and  Tungsten  resemble  each  other  closely  and  induce  t3'^pical 
metallic  poisoning. 

Uranium,  in  addition  to  the  ordinary  features  of  metafile  into.xication,  causes 
some  glj'cosuria,  the  sugar  often  amountmg  to  1  per  cent,  in  the  urine.  In 
addition,  dropsy  occurs  in  animals  poisoned  with  this  metal,  partly  from  the 
changes  in  the  renal  tubules,  but  cliiefij^,  it  is  said,  from  a  destructive  effect  on 
the  smaller  vessels. 

Selenium  and  Tellurium  are  classed  along  with  sulphur  in  chemical  systems, 
but  the  salts  of  teUuric,  selenious  and  selenic  acid  induce  symptoms  resembling 
those  of  the  heavy  metals  and  arsenic  in  many  points,  and  may  be  inserted  in 
this  series.  In  the  frog  the  sj'mptoms  are  those  of  central  nervous  paralysis, 
and  later  of  heart  failure.     In  mammals  ^•omiting,  purging,  somnolence,  flys- 


0,78  THE  HEAVY  METALS 

pnoea,  tonic  and  clonic  convulsions  have  been  noted,  and  the  stomach  is  found 
somewhat  reddened,  the  mucous  membrane  of  the  intestine  swollen  and  dysen- 
teric, while  the  kidnej's  seem  less  affected.  The  perspiration  is  prevented  by 
tellurates,  apparently  from  paralysis  of  the  terminations  of  the  secretory 
nerves  similar  to  that  induced  by  atropine.  An  early  symptom  of  poisoning 
with  these  bodies  is  a  garhc  odor  in  the  breath,  and  many  of  the  organs  are 
found  of  a  grayish  color  after  death,  and  possess  this  odor.  Hofmeister  has 
shown  that  these  salts  are  reduced  to  metallic  selenium  and  tellurium  in  the 
body,  and  that  afterward  methyl  compounds  (Te(CH3)2,  Se(CH3)2)  are  formed. 
These  are  volatile,  and,  excreted  by  the  lungs,  urine  and  faeces,  give  the  dis- 
agreeable odor.  The  synthesis  of  methyl-tellurium  is  one  of  the  few  known  cases 
in  which  a  compound  with  methyl  is  formed  in  the  animal  body,  and  is  of  great 
biological  importance.  All  the  selenium  and  tellurium  is  not  excreted  in  this 
form,  for  some  of  it  appears  in  the  urine,  and  probably  in  the  faces,  in  other 
combinations. 

Tellurates  have  been  advised  in  therapeutics  to  prevent  excessive  sweating, 
and  certainly  have  this  effect,  but  are  not  to  be  recommended,  as  the  strong 
garlic  odor  of  the  breath  persists  for  days  or  even  weeks  after  one  dose. 

Osmic  Acid  has  been  recommended  as  an  injection  into  the  nerves  in  neu- 
ralgia. It  is  an  intensely  irritant  substance,  and  seems  to  induce  nephritis 
and  diarrhoea  when  absorbed.  The  greater  part  of  the  poison  is,  however, 
deposited  as  a  black  powder  at  the  point  of  injection,  owing  to  its  being  reduced 
by  the  tissues. 

Cerium  was  formerly  used  in  therapeutics  in  the  sickness  of  pregnancy  and 
similar  conditions,  but  is  valueless.  The  cerium  double  salts  injected  into  the 
bloodvessels  of  animals  are  said  to  depress  the  heart  and  ca\ise  ecchymoses 
in  the  stomach  and  bowel,  and  nephritis.  The  oxalate  is  insoluble  and  is  not 
absorbed  from  the  ahmentary  tract. 

Thorium  is  a  very  inactive  metal,  which  does  not  seem  to  be  absorbed  from 
the  alimentary  tract. 

Bibliography. 
Cadmium. 

[Marmi.     Ztschr.  f.  rat.  Med.,  xxix,  p.  125. 

[Wkeeler.     Boston  Med.  and  Surg.  Journ.,  xcv,  p.  434. 

Nickel  and  Cobalt. 

Sluarl.     Journ.  of  Anat.  and  Phys.,  xvil,  p.  89.     Arch.  f.  exp.  Path.  u.  Pharm..  xviii, 
p.  151. 
[Rohde.     Arch.  f.  Hygiene,  ix,  p.  331. 
[Hiibner.     Arch,  internat.  de  Pharrnacodyn.,  ix,  p.  339. 
[Wohlwill.     Arch.  f.  exp.  Path.,  Ivi,  p.  404. 
[Armit.     Journ.  of  Hygiene,  vii,  p.  525;    viii,  p.  565. 

Tin. 

White.     Arch.  f.  exp.  Path.  u.  Pharm.,  xiii,  p.  53. 

Lehtnann.     Arch.  f.  Hygiene,  xlv,  p.  88. 

Buchanan  and  Schryver.     Local  Government  Reports,  1908. 

Thallium. 

Luck.     Inaug.  Diss.,  Dorpat,  1891. 

liichet.     Comptes  rend,  de  la  Soc.  de  Biol.,  1899,  p.  252. 
Bullard.     Boston  Med.  and  Surg.  Journ.,  1902  (2),  p.  589. 
Luzzalo.     Biochem.  Centralbl.,  ii,  p.  86. 

Vanadium. 

Priestley.     Phil.  Trans,  of  Roy.  Soc,  clxvi,  p.  495. 

Garngce  and  Larinuth.     Journ.  of  Anat.  and  Phys.,  xi,  pp.  235,  2.'")1. 

Dowdeswcll.     Journ.  of  Phys.,  i,  p.  257. 

Jackson.     Journ.  of  Pharmacology,  iii,  p.  477;    iv,  p.  1. 


MINOR  METAL3  679 

Tungsten. 

Bernstcin-Kohan.     Kobcrt's  Arbeit,  a.  d.  pharm.  Instit.  zu  Dorpat,  v,  p.  42. 

Uranium. 

Woroschilsky.     Kobert's  Arbeit,  a.  d.  pharm.  Instit.  zu  Dorpat,  v,  p.  1. 

Chittenden.     Studies  from  the  Lab.  of  Phys.  Chem.  of  Sheffield  Scientific  School,  i,  ii,  iii. 

Fleckseder.     Arch.  f.  exp.  Path.  u.  Pharm.,  Ivi,  p.  54. 

Jackson  and  Mann.     Amer.  Journ.  of  Physiol.,  xxvi,  p.  381. 

Selenium  and  Tellurium. 

Czapek  u.  Weil.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxii,  p.  438. 
Hofmeister.     Ibid.,  xxxiii,  p.  198. 

Gies  and  Mead.     Amer.  Journ.  of  Phys.,  v,  p.  104;    Philadelphia  Med.  Journ.    1901, 
p.  5GG. 


PART  IV. 


I.    COD-LIVER  OIL. 

Cod-liver  oil  has  long  been  used  by  the  fishermen  of  the  North  Sea 
as  a  remedy  in  children's  diseases,  and  was  introduced  into  medicine 
in  the  beginning  of  last  century,  but  became  generally  used  only  in 
the  last  fifty  years. 

It  is  obtained  from  the  liver  of  the  cod-fish  (Gadus  morrhua),  and 
probably  from  other  members  of  the  genus.  Formerly  the  livers  were 
left  to  decompose  and  the  oil  set  free  by  the  breaking  up  of  the  cells 
was  collected.  It  had  a  most  disagreeable  odor  and  taste,  however, 
and  many  patients  could  not  be  induced  to  take  it,  while  those  who 
were  courageous  enough  to  swallow  it,  often  suffered  from  eructation 
and  diarrhoea  afterward.  This  method  w^as  therefore  soon  replaced 
by  the  "steam-process,"  in  which  the  oil  is  melted  out  of  the  fresh 
livers,  yielding  an  oil  of  much  lighter  color,  and  with  much  less  dis- 
agreeable smell  and  taste.  Quite  recently  a  new  process  has  been 
introduced  by  w^hich  the  oil  is  extracted  by  steam,  without  being  exposed 
to  the  air,  and  it  is  stated  that  oil  thus  obtained  is  less  disagreeable 
than  any  other. 

The  cod-liver  oils  used  in  therapeutics  differ  considerably  in  appear- 
ance and  in  composition,  the  older  preparations  being  brownish  in 
color  and  having  a  strong  fislw  odor  and  a  somewhat  acrid,  disagree- 
able taste,  while  the  oil  prepared  by  the  more  recent  processes  is  pale 
yellow  in  color,  and  has  much  less  odor  and  a  bland  taste. 

Cod-liver  oil,  like  the  oils  derived  from  the  livers  of  other  animals, 
contains  the  ordinary  glycerin  oleate,  palmitate  and  stearate,  and  also 
glycerin  esters  of  some  unidentified  non-saturated  acids,  along  with 
lecithin.  Some  free  fatty  acid  is  generally  found  in  it,  the  darker 
preparations  containing  some  4-7  per  cent.,  the  pale  yellow  oil  less 
than  1  per  cent.,  as  a  general  rule. 

Iodine  and  bromine  are  present  in  traces,  apparent!}^  very  much  smaller 
in  amount  than  is  generally'  believed.  The  usual  statement  is  that  0.03-0.04 
per  cent,  of  iodine  and  0.003-0.005  of  bromine  exists  m  the  oil,  but  some  oils 
have  been  found  to  contain  only  about  one-hundredth  of  this  amount  of  iodine. 

Phosphorus  is  found  in  traces  in  some  oils,  in  an  organic  combination,  not 
in  the  free  state.  A  small  percentage  of  cholesterin  is  often,  not  invariably, 
present,  and  bile  acids  and  pigments  have  been  said  to  occur,  but  this  seems 
incorrect.  A  number  of  bases  have  been  found  in  cod-liver  oil  by  Gautier, 
especially  in  the  darker  colored  varieties,  while  the  pale  yellow  oil  contains 
little  or  none. 

Cod-liver  oil  has  no  very  distinct  action  when  taken  in  ordinary 
doses,  while  in  large  quantities  it  has  a  tendency  to  cause  eructation, 

( fisi ) 


682  •        COD-LIVER.  OIL 

nausea,  and  diarrhoea.  Taken  repeatedly,  it  increases  the  weight  and 
strength  and  improves  the  general  condition.  The  same  effects  are 
obtained  in  healthy  persons  by  the  use  of  good  food  and  fats,  but  deli- 
cate patients  who  are  unable  to  digest  ordinary  animal  fats  are  able 
to  take  cod-liver  oil.  Its  effects  are  obviously  those  of  an  easily  assimi- 
lable food,  and  it  is  not  a  drug  in  the  ordinary  sense  of  the  term,  and  has 
therefore  no  place  in  pharmacology  properly  speaking,  but  should  be 
classed  along  with  other  foods.  It  is  always  treated  as  a  drug,  however, 
because  it  has  often  been  supposed  to  have  some  specific  efj'ect  quite 
apart  from  ordinary  foods.  It  is  generally  believed  to  differ  from 
ordinary  fats  in  being  more  readily  assimilable,  but  the  explanation  of 
this  fact  is  by  no  means  agreed  upon,  for  though  it  is  often  said  to  be 
more  rapidly  absorbed  from  the  intestine,  there  is  little  reliable  evidence 
that  such  is  the  case.  A  few  experiments  have  been  carried  out,  but  by 
no  means  enough  to  establish  the  truth  of  the  statement  satisfactorily, 
and  the  chief  argument  brought  forward  in  its  support  is  that  cod-liver 
oil  forms  an  emulsion  in  the  test-tube  more  rapidly  than  other  oils.  It 
is  undoubtedly  well  borne  by  the  stomach,  but  it  has  not  been  often 
compared  with  other  oils  in  regard  to  this  point,  and  it  is  still  impossible 
to  state  that  other  oils  administered  with  the  same  care  as  cod-liver  oil 
are  not  equally  successful  remedies. 

Buchheim  explained  that  cod-liver  oil  formed  an  emulsion  rapidly 
on  account  of  the  free  acid  it  contained,  and  this  has  generall}'  been 
put  forward  as  accounting  for  its  effects  in  therapeutics.  As  far  as 
regards  the  old  dark-colored  oils,  this  explanation  may  hold  good,  but 
the  pale  oil  now  used  in  therapeutics  often  contains  less  free  acid  than 
ordinary  olive  oil.  Some  enthusiastic  supporters  of  Buchheim's  theory 
have  therefore  asserted  that  the  pale  oil  does  not  give  the  same  results 
as  the  older,  less  pure,  acid  preparations,  but  this  is  not  the  general 
opinion  of  the  medical  profession. 

The  older  explanations  started  from  the  view  that  cod-liver  oil  is  a  drug, 
that  the  oil  itself  is  only  a  means  to  administer  certain  active  principles  con- 
tained in  it.  Thus  iodine  and  pliosphorus  were  in  turn  supposed  to  be  the 
essential  constituents,  but  have  both  been  shown  to  be  present  in  too  small 
quantities  to  be  of  any  effect.  More  recently  cholcsterui  has  been  suggested 
as  the  curative  agent,  but  it  is  present  in  smaller  quantities  in  cod-liver  oil  than 
in  many  other  foods.  The  bases  are  apparently  quite  inactive  in  the  quantities 
contained  in  the  oil. 

Several  substitutes  for  cod-liver  oil  have  been  proposed,  such  as  Lipanin 
(v.  Mering),  which  is  formed  from  olive  oil  by  the  addition  of  6  per  cent,  of 
oleic  acid,  and  which  was  suggested  by  the  theory  that  cod-liver  oil  owes  its 
rapid  absorption  to  the  presence  of  free  acid. 

On  the  whole,  cod-liver  oil  has  not  been  shown  to  have  any  action 
apart  from  that  of  an  easily  digested  food,  and  its  superiority  to  some 
other  fats  and  oils  has  not  been  satisfactorily  established. 

Preparations. 

Oi.EiiM  MoRuiiu.K  (U.  S.  P.,  B.  p.),  cod-liver  oil,  Oleum  Jocoris  Aselli,  a 
lixcd  oil  oblaiiu'd  from  the  fresh  livers  of  Cladus  morrluia  and  of  otlier  species 


COD-LIVER  OIL  683 

of  Gadus — a  pale  j^ellow,  thin,  oily  liquid,  with  a  peculiar,  slighlly  fishy,  but 
not  rancid,  odor,  and  a  bland,  slightly  iishy  taste.    16  c.c.  (4  fl.  drs.). 
Emulsum  Olei  Morrhua:  (U.  S.  P.),  50  per  cent.    8  c.c.  (2  fl.  drs.). 

Therapeutic  Uses. — Cod-liver  oil  is  used  in  chronic  wasting  diseases, 
such  as  tuberculosis,  scrofula,  rickets,  and  some  forms  of  syphilis. 
It  is  especially  beneficial  in  the  earlier  stages  of  pulmonary  phthisis, 
but  has  no  specific  virtues  here  or  elsewhere  apart  from  those  of  an 
easily  digested  fat.  In  all  forms  of  malnutrition  and  delicacy  in  children 
it  is  largely  used,  and  undoubtedly  causes  a  considerable  increase  in 
weight,  but  care  must  be  taken  that  it  does  not  disturb  the  digestion, 
especially  if  the  darker  oils  are  used.  In  some  persons  pure  cod-liver 
oil  always  induces  nausea,  but  a  much  larger  number  refuse  to  take  the 
brown  oil.  In  most  cases  the  light-colored  oil  is  taken  readily,  especially 
if  the  dose  be  small  at  first  (a  teaspoonf ul) .  When  there  is  dyspepsia  or 
a  tendency  to  diarrhoea,  cod-liver  oil  should  be  given  with  caution,  and 
it  is  generally  prescribed  only  in  cold  w^eather,  as  it  is  found  that  patients 
have  a  distaste  for  it  in  summer.  When  fever  or  acute  disease  is  present, 
cod-liver  oil  is  generally  found  of  little  value,  perhaps  on  account  of 
the  disturbed  condition  of  the  digestion.  Cod-liver  oil  should  not  be 
forced  on  patients;  when  it  continues  to  induce  nausea  and  eructation 
after  a  fair  trial,  it  should  be  abandoned. 

Innumerable  means  have  been  proposed  to  conceal  the  odor  and 
taste,  but  it  is  generally  conceded  that  when  possible  the  pure  oil  is 
better  given  alone.  When  patients  cannot  be  induced  to  take  it  in 
this  way,  some  volatile  oil,  ether,  or  brandy  may  be  added  to  it;  sac- 
charine has  also  been  used  to  sweeten  it.  Creosote  is  sometimes  mixed 
with  cod-liver  oil  in  cases  of  phthisis,  or  an  emulsion  is  formed  con- 
taining cod-liver  oil,  some  flavoring  substance,  iron,  hypophosphites, 
or  calcium.  Extract  of  malt  and  cod-liver  oil  form  a  common  mixture, 
and  are  the  basis  of  many  patented  emulsions. 

In  general,  the  pale  oil  is  preferred,  but  it  must  be  added  that  some 
physicians  persist  in  the  use  of  the  darker  forms,  which  contain  more 
bases  and  more  free  acid,  but  have  a  much  more  disagreeable  taste 
and  smell,  and  are  more  liable  to  disturb  the  digestion.  Of  the  sub- 
stitutes for  cod-liver  oil,  lipanin  has  little  taste  and  is  generally  taken 
readily.    It  may  be  given  shaken  up  in  milk  or  formed  into  an  emulsion. 

Bibliography. 

Naumann.     Arch,  der  Heilkunde,  1865,  p.  536. 

Buchheim.     Arch.  f.  exp.  Path.  u.  Pharm.,  iii,  p.  118. 

V.  Mering.     Therap.  Monatsh.,  1888,  pp.  49  and  233. 

Salkowski.     Ibid.,  1888,  p.  230. 

Hauser.     Ztschr.  f.  klin.  Med.,  xiv,  p.  543;    xx,  p.  239. 

Lowenthal.     Arch.  f.  Anat.  u.  Phys.,  1897,  p.  258. 

Mesereau.     New  York  Med.  Journ.,  1899,  ii,  p.  11. 

Sternberg.     Ztschr.  f.  khn.  Med.,  xxii,  p.  295. 

Bouillot.     Compt.  rend,  de  I'Acad.  des  Scien.,  cxv,  p.  754. 

Gautier  et  Mourgues.     Lcs  Alcaloides  de  Huile  des  Foies  de  Morue,  Paris,  1890. 

Heyerdahl.     F.  Pekel  MoUer's  Cod-liver  Oil  and  Chemistry,  London,  1S95,  p.  88. 

Wells.     Brit.  Med.  Journ..  Oct.  18,  1902. 


GS4  MENSTRUA  AND  MECHANICAL  REMEDIES 

Hypophosphites  and  Glycerophosphates. 

The  hypophosphites  have  been  used  in  therapeutics  in  the  behef  that  they 
had  some  special  influence  on  nutrition.  They  were  formerly  supposed  to 
be  oxidized  in  the  tissues  to  the  phosphates,  but  this  has  been  shown  to  be 
incorrect,  as  practically  the  whole  of  the  hypophosphite  administered  can 
be  recovered  unchanged  from  the  urine.  No  entirely  satisfactory  work  on 
the  effects  of  these  salts  on  the  nutrition  has  been  done,  but  there  is  no  ground 
to  suppose  that  they  have  any  further  action  than  the  other  indifferent  salts, 
such  as  the  chlorides.  The  hypophosphites  of  sodium,  potassium,  and  calcium 
along  with  hyjiophosphorous  acid  are  contained  in  the  Syrupus  Ilypophosphitum 
(U.  S.  P.),  which  has  been  used  in  doses  of  2  fl.  drs.  in  various  conditions  of 
malnutrition  and  cachexia  in  the  popular  belief  that  it  improves  digestion  and 
assimilation.    This  is  quite  without  foundation. 

The  glycerophosphates  have  been  employed  in  thcrapeuti(!s  in  the  same  way 
as  the  hypophosphites,  there  being  some  vague  idea  that  they  imjjrove  nutrition 
and  supply  organic  phosphorus  compounds  to  the  nervous  system.  As  a  matter 
of  fact  they  are  rapidly  decomposed  and  the  phosphate  is  excreted  in  the  urine 
and  stools  as  inorganic  salts,  while  the  glycerin  undergoes  combustion;  the 
administration  of  glycerophosphates  has  thus  no  more  effect  than  that  of 
glycerin  and  inorganic  phosphates.    Their  use  in  therapeutics  is  nil. 

II.     MENSTRUA  AND  MECHANICAL  REMEDIES. 

Oleum  Theobromatis  (U.  S.  P.,  B.  P.),  cacao-butter,  a  fixed  oil  expressed 
froni  the  seeds  of  Theobroma  cacao,  forms  a  yellowish-white  solid  having  a 
faint,  agreeable  odor  and  a  bland,  chocolate  taste.  It  melts  a  little  below  the 
temperature  of  the  body.  Cacao-butter  is  used  almost  exclusively  to  form 
suppositories,  in  which  astringents  and  other  remedies  are  incorporated.  When 
introduced  into  the  rectum  they  melt  and  the  active  principle  is  liberated. 

Keratin  (not  official)  is  a  substance  obtained  from  horns,  hoofs,  nails,  etc., 
which  is  insoluble  in  the  gastric  juices,  but  is  dissolved  by  the  alkaline  jjan- 
creatic  secretion.  It  is  used  to  coat  pills  which  it  is  desired  to  protect  from 
disintegration  in  the  stomach. 

KaoUnum  (B.  P.,  U.  S.  P.),  or  porcelain  clay,  is  used  in  the  formation  of 
pills  containing  easily  reduced  bodies,  such  as  silver  nitrate  or  potassium  per- 
manganate. Mixed  with  the  ordinary  vegetable  excipients,  such  as  confection 
of  roses,  or  extract  of  liquorice  or  gentian,  these  salts  would  be  reduced  at  once. 
Kaolin  is  an  aluminium  silicate  and  forms  a  soft  whitish  powder  insoluble  in 
water  or  dilute  acids. 

Cataplasma  Kaolini  (U.  S.  P.),  kaolm  moistened  with  glycerin  and  applied 
as  a  poultice. 

Sapo  (U.  S.  P.),  Sapo  Durus  (B.  P.),  hard  soap,  white  Castile  soap,  is  pre- 
pared from  soda  and  oUve  oil. 

Sapo  Mollis  (U.  S.  P.,  B.  P.),  soft  soap,  sapo  viridis,  a  soap  made  from  potash 
and  olive  oil. 

Sapo  Animalis  (B.  P.),  curd  soap,  soap  made  with  sodium  hydroxide  and 
purified  animal  fats  consisting  chiefly  of  stearin;  it  contains  about  30  per 
cent,  of  water. 

These  soaps  are  used  in  therapeutics  as  ingredients  of  liniments  and  plasters. 
Water  containing  soap  is  often  thrown  into  the  rectum  as  an  enema,  and  in 
infants  a  soapstick  inserted  into  the  anus  generally  jjrovokes  evacuation  of  the 
bowels  in  a  few  minutes. 

Soaps  inii)regnated  with  antiseptics,  such  as  perchloride  of  mercury,  carbolic 
acid,  tar,  or  iodine,  are  often  used  to  clisinfect  the  hands. 

The  chief  preparations  in  which  soap  is  used  in  the  pluuinncoixpias  are: 

Emplmlrum  Saponis  (U.  S.  P.,  H.  P.),  soap  jilaster. 


MENSTRUA   AND  MECHANICAL  REMEDIES  685 

Linimentim  Saponis  (U.  S.  P.,  B.  P.),  soap  limiment. 
Lini7)icntum  Sapoiiis  Mollis  (U.  S.  P.)- 

The  liniments  consist  of  alcohol  with  soap  in  suspension,  perfumed  with 
volatile  oils,  and  are  mildly  irritant  to  the  skin.  They  are  used  largely  as  bases 
for  other  liniments. 

The  use  of  the  oils,  fats  and  glycerin  as  vehicles  for  the  application  of  remedies 
to  the  skin  has  been  mentioned  already  (page  46).  They  may  also  be  used  to 
dissolve  remedies  which  are  insoluble  in  water,  but  which  are  to  be  given  by 
the  mouth,  such  as  phosphorus  (in  oil). 

Wax  (cera  alba,  cera  flava)  is  used  chiefly  to  increase  the  consistency  of 
ointments.  A  special  series  of  preparations  somewhat  stiffer  than  the  ointments 
are  the  cerates  of  the  U.  S.  P. 

Plasters  are  sticky,  adhesive  substances  which  are  chiefly  used  to  give 
mechanical  support,  but  which  are  often  unpregnated  with  active  remedies  in 
order  to  eUcit  their  local  action  on  the  skin.  The  basis  of  many  of  the  plasters 
is  lead  plaster,  which  is  olDtained  by  the  action  of  lead  oxide  on  olive  oil  and 
consists  for  the  most  part  of  lead  oleate. 

Emplastrum  Plumbi  (U.  S.  P.,  B  P.),  lead  or  diachylon  plaster. 
Emplasirum  Adhccsivum  (U.  S.  P.),  Resmce  (B.  P.),  adhesive  plaster. 
Emplastrum  Saponis  (U.  S.  P.,  B.  P.),  soap  plaster. 
Emplastrwn  Belladonnw  (U.  S.  P.,  B.  P.),  belladonna  plaster. 
Emplastrum  Calefaciens  (B.  P.),  warming  plaster  (page  84). 
Emplastrum  Cantharidini  (B.  P.)  (page  84). 
Emplastrum  Hijdrargyri  (U.  S.  P.,  B.  P.),  mercury  plaster. 
Court  plaster  is  formed  from  isinglass,  the  dried  swimming  bladder  of  several 
species  of  sturgeon,  which  is  dissolved  in  water,  alcohol  and  glycerin  and  painted 
on  taffeta.     Isinglass  differs  from  lead  plaster  and  its  derivatives  in  being 
transparent,  so  that  if  it  be  spread  on  a  flesh-colored  cloth,  it  disfigures  the  hands 
and  face  less  than  the  others. 

Lead  plaster,  adhesive  plaster  and  isinglass  plaster  are  used  only  to  cover 
and  protect  cuts  and  abrasions,  and  to  keep  the  edges  of  wounds  in  apposition. 
The  adhesive  plaster  and  isinglass  plaster  are  superior  to  lead  plaster,  as  they 
stick  more  firmly.  It  is  perhaps  unnecessary  to  add  that  plasters  are  always 
apphed  spread  on  cloth.  Belladonna  plaster  is  said  to  lessen  the  secretion  of 
perspiration  and  of  milk.  The  menthol  plaster  has  some  irritant  action  and 
this  is  of  course  more  marked  in  the  case  of  the  warming  plaster  and  cantharidin 
plaster.  Some  mercury  is  absorbed  when  the  mercury  plaster  is  applied  to  the 
skin,  but  this  method  of  administration  allows  of  even  less  accurate  dosage 
than  inunction,  and  is  seldom  used. 

Another  series  resembling  the  plasters  in  their  sphere  of  usefulness  is  formed 
by  the  CoUodia.  Their  basis  is  pyroxylin,  or  soluble  gun-cotton,  which  is 
formed  from  cotton  by  the  action  of  sulphuric  and  nitric  acids,  and  which 
consists  of  a  mixture  of  nitrates  of  cellulose.  Collodion  is  formed  by  dissolving 
pyroxylin  in  a  mixture  of  alcohol  and  ether.  When  these  evaporate,  there 
remains  a  fine  layer  of  pyroxyhn,  which  protects  the  surface  to  which  it  is 
applied  and  gums  the  edges  of  slight  cuts  together.  This  collodion  is  rendered 
less  brittle  by  the  addition  of  Canada  turpentine  and  castor  oil  in  small  pro- 
portions, and  is  then  known  as  flexible  collodion.  A  blistering  collodion  is 
formed  by  the  addition  of  cantharidin  to  the  flexible  preparation.  Another 
preparation  contains  tarmic  acid. 

Pyroxylinum  (U.  S.  P.,  B.  P.),  soluble  gun  cotton,  coUoxylin. 
Collodium  (U.  S.  P.,  B.  P.),  collodion. 
Collodium  Flexile  (U.  S.  P.,  B.  P.),  flexible  collodion. 

Collodium  Cantharidatum  (U.  S.  P.),  Collodium  Vesicans  (B.  P.),  blistering 
collodion. 
Collodium  Stypticum  (U.  S.  P.),  contains  20  per  cent,  of  tannic  acid. 
Instead  of  collodion,  india-rubber,  Elastica  (U.  S.  P.),  may  be  dissolved  in 
chloroform  and  apphed  in  the  same  way. 

Calcii  Sidphas  Exsiccatus  (U.  S.  P.),  Dried  Gypsum,  used  to  impregnate 
bandages,  which  then  become  hard  and  immovable. 


CLASSIFICATION  OF  DRUGS  ACCORDING  TO 
THEIR  THERAPEUTIC  USES. 


Drugs  applied  for  their  local  action  to 
the  skin,  wounds,  or  visible  mucous 
membranes. 

Corrosives  or  caustics. 

Potash,  542 

Mercury  nitrate,  639 

Silver  nitrate,  667 

Zinc  chloride,  664 

Niti'ic  acid  and  other  acids,  554 

Chromic  acid,  675 

Burnt  alum,  673 

Ai'senic,  599 

Trichloracetic  acid,  555 

Ammoniated  mercury  and  other 

mercury  preparations,  639 
(Carbolic  acid,  136) 
(Salicylic  acid,  493) 

Disinfectants  and  antiseptics. 

General  'principles,  124-127 
Hydrogen  peroxide,  140 
Permanganate  of  potassium,  142 
Carbolic  acid,  136 
Corrosive    subhmate    and    other 

mercury  salts,  139 
Silver  nitrate,  139 
Zinc  chloride,  664 
Boracic  acid,  143 
Iodine,  149 
Iodoform,  lodol,  149 
Cresol  (lysol),  137 
Tar,  156 

Salicylic  acid,  493 
(Benzoic  acid,  501) 
(Alcohol,  188) 
(Volatile     oils     (thymol,     euca- 

lyptol,  etc.)) 

Astringents. 

Tannic  acid  series,  113 

Iron  preparations,  e.  g.,  sulphate, 

648 
Bismuth  preparations,  670 
Lead  acetate,  657 
Zinc  sulphate  and  oxide,  663 
Copper  sulphate,  661 
Alum,  673 
(Alcohol,  188) 


Slijpiics, 

Soluble  astringents  (see  above). 
Iron  perchloride,  647 
Silver  nitrate,  667 
Burnt  alum,  673 

To  contract  vessels  and  reduce  hemor- 
rhage and  swelling. 
Adrenaline,  371 

Emollients  or  protectives. 

Emollients,  46 
Plasters  and  CoUodia,  685 
Dusting-powders  —  starch,  tal- 
cum, chalk,  and  many  insol- 
uble metallic  powders,  which 
may  also  be  slightly  astrin- 
gent, 49. 

Local    anodynes    and    analgesics   for 
pain  and  itching. 

Bicarbonate  of  potassium,  542 
Cocaine,     Eucaine,     Orthoform, 

etc.,  358-363 
Carbolic  acid,  136 
Chloretone,  233 
(Prussic  acid,  453) 
(Atropine,  333) 
(Aconite,  429) 
Some  volatile  oils  (in  dentistry), 

Local  anesthetics. 

Cold  by  evaporation  of  ether 
ethyl  chloride,  carbon  dioxide, 
etc.,  70 

Cocaine,  etc.,  358-363 

To  disinfect  rooms  and  other  inanimate 
objects. 

Chlorine,  166 
Sulphur  dioxide,  165 
Formaldehyde,  164 
Unslaked  lime,  563. 
Carbolic  acid  (crude),  136 
Tar,  156 
Moist  heat. 


6SS 


rUl-h'M'I'Ji'TlC  (  LASSIFICATION 


n.  Drugs  used  for  affections  of  the  ali- 
mentary tract. 

JNIouTH  AND  TnHOAT  (sco  Scction  I). 
Demulcents,  43 

Chlorates,  14.5 
-  Ammonium  chloride,  508 
Cubebs,  160 

Aslringenls. 

Tannin  group  in  solution  or 

lozenges,  113 
(Claret,  118) 

Antiseptics. 

Boric  acid,  143 
Sulphites,  53,5 

Thymol  and  other  volatile 
oils. 

To  lessen  salivation. 
Atropine,  330 

Flavoring  substa7iccs. 
Sugars,  49 

Volatile  oils  series,  57 
Acids  (citric),  556 
Syrup  of  Tolu,  Ginger,  etc. 
Saccharin,  50 

Stomach. 

Digestives. 

Pepsin,  Papain,  etc.,  55 
Hydrochloric  acid,  556 

Emetics  (see  p.  436). 
Common  salt,  511 
Mustard,  82 
Warm  water. 
Apomorphinc,  436 
Ipecacuanha,  439 
Tartar  emetic,  621 
Copper  sulphate,  661 
Zinc  sulphate,  663 
(Alum,  673) 
(Ammonium  carbonate,  548) 

To  lessen  irritation  and  vomiting. 
Opium,  252 

Chloral,  Chlorotone,  235 
Bromides,  265 
Lime-water,  563 
Bismuth,  671 
Cold  (ice). 

Carbonic-acid  water,  571 
Demulcents,  43 
(Prussic  acid,  453) 

To  lessen  acidity,  antacids. 

Potassium  and  Sodium  car- 
bonates and  Bicarbonates, 
542 

Magnesia  and  Magnesium 
carbonate,  542 

Lime-water  and  chalk,  563 


Tu  increase  secretion,  bitters.  ' 

Simple  bitters,  51 

Nux  vomica,  Strychnine,  275 

Cinchona  and  Quinine,  468 

Carminatives. 

Volatile  oil  carminatives,  61 
Ether,  70 

Alcoholic  preparations,  188 
Carbonic  acid  waters,  571 
Carbonates     and     Bicarbo- 
nates, 542 
Bitters,  51 
Camphor,  69 
Charcoal,  571 
Ammonium  carbonate,  548 
Arsenic,  600 


Intestine. 

2'o  -promote  digestion. 

(Pancreatin,  55) 
(Diastase,  57) 

To    promote    evacuation — purga- 
tives. 

Mild  aperients — Castor  Oil, 
Sulphur,  Phenol  phthalein, 
90 
Rhubarb  and  Aloes  group, 

93 
Jalap  and  Colocynth  group, 

96 
Saline  purgatives,  107 
Agar-agar,  107 
Liquid  paraffin,  107 
Mercurial    purgatives— Cal- 
omel and  Metallic  prepar- 
ations, 634 
Enemata. 

Glycerin  suppositories,  92 
Physostigmine,  349 
Pituitary  extract,  384 
Totrachiorphenolphthalein, 
91^ 

To    lessen    movement    and    relax 
spasm. 

Opium  and  Morphine,  252 
Tannic  acid  scries,  109 
Lime-water,  563 
Lead  acetate,  657 
Bisnuith,  671 

Atropine   (to  relax  spasm), 
332 

To  destroy  parasites — anthelmin- 
tics. 


Male  fern,  116 
Pelleticrine,  119 
Cusso,  etc.,  lis 
Santonin,  121 


I 


THERAPEUTIC  CLASSIFICATION 


CiSO 


Calomel,  634 
Salol,  157 
Thymol,  120 
Naphthol,  155 
(Some  volatile  oils.) 
(Chloroform,  70) 
(Quassia  enema,  53) 

Disinfedants  and  antiseptics. 

See  Discussion,  p.  128. 

(Vegetable  and  Saline  pur- 
gatives.) 

Mercurial  purges — Calomel, 
634 

Salol,  157 

III.  Drugs  used  for  their  effects  on  the 
circulation. 

Heart. 

To  strengthen  contraction. 
Digitalis  group,  418 

In  auricular  fibrillation. 
Digitalis  group,  416 

To  accelerate  pulse. 

Atropine,  331 
(Caffeine,  288) 

To  sloio  the  pulse. 

Digitalis  group,  416 
(Aconite,  429) 

Vessels. 

To  contract  calibre  and  raise  blood- 
pressure. 

(Digitalis,  418) 

Strychnine,  276 

Caffeine,  288 

Ergot,  379 

Adrenaline  (intravenously), 

371 
Pituitary  extract,  384 

To  relax  vessels  and  lower  blood- 
pressure  {angiyia  pectoris). 

Nitrite  series,  393 
Purgatives,  99 

To  arrest  internal  hemorrhage. 

(seep.  380). 
Ergot,  380 
Adrenaline,  371 
Pituitary  extract,  384 
Nitrites,  393 
Opium    and    Morphine    (to 

allay  restlessness),  252 
(Calcium  is  useless,  562) 


To    remove   fluid    {dropsj,.    ana- 
sarca) . 

Digitalis  series,  418 
Diuretics  (see  Section  IV). 
Saline  cathartics,  107 
Sudorifics — Pilocarpine,    hot 

and  cold  packs,  343 
(Vegetable  cathartics,   96) 

IV.  Drugs  used  for  their  effects  on  the 
genito-urinary  system. 

To  increase  the  flow  of  urine  (diuretics). 

Caffeine  and  Theobromine,  288 
Digitalis  and  Squills,  420 
(Turpentine,  Uva  Ursi,   Scopar- 

ius.) 
(Pituitary  extract,  354) 
Saline  diuretics  and  Urea,  294 
Iodides  of  the  alkalies,  524 
Carbonates,  543 
Mercury — calomel  and  blue  pill, 

634 

To  render  the  urine  less  acid. 

Alkali   carbonates   and   bicarbo- 
nates,  543 
Acetates,  545 
Citrates,  545 

To  make  the  urine  more  acid. 

Acid  sodium  phosphate,  555 

Acids,  554 

(Ammonium  benzoate,  etc.,  501) 

To  render  the  urine  antiseptic. 

(See  pp.  129,  159). 
Copaiba  series,  158 
Urotropine,  160 
Salol  and  Salicylates,  492 
Borax,  145 
Local     antiseptics,     astringents, 

anodynes,    caustics,    etc.,    are 

used     in     the     urethra     and 

bladder. 

To  promote  contraction  of  the  uterus 
(ecbolics) . 

Ergot,  379 
Quinine,  409 
Pituitary  extract,  384 
(Pilocarpine,  343) 
(Hydrastinine,  387) 
Atropine  is  said   to  allay  spas- 
modic contraction. 

To    promote    menstruation    (emmena- 
gogues). 

Iron,  646 

Aloes,  99 
(Myrrh). 

Hydrastis,  387,  is  said  to  lessen 
menstrual  flow. 


44 


GOO 


Til  ERA  PE  UTIC  CLA  SSIFICA  TION 


V.  Drugs  used  for  their  effects  on  the 
respiratory  system. 

To  siimulale  the  respiraiory  centre. 

Atropine,  331 

Caffeine,  288 

Strychnine,  276 

Aspidosperma,  455 

Carbonic  dioxide,  5-10  per  cent., 

573 
See  also  Oxygen,  575 

To  reduce  the  irritahililij  of  the  cndre 
in  cough. 

Opium,  Morpliine,  and  Codeine, 

251 
(?Ieroine,  252) 
Chloral  series,  235 
Bromides  of  tiie  alkahes,  265 

To  increase  and  liquefy  the  hro)irhi(d 
secretion.    (See  p.  4;]6.) 

Ipecacuanha,  439 
Tartar  emetic,  621 
Squills,  423 
Apomorphine,  436 
Senega,  449 

Ammonium  carbonate,  548 
Iodides  of  the  alkalies,  524 
(Lobelia,  312) 

To  lessen  the  secretion  of  the  bronchi  (?). 

Benzoic     acid,     Benzoin,     Tolu 

Balsam,  501 
Ammonium   chloride,   518 
(Cubebs,  1()0) 

To  relax  bronchial  spasm  in  astlmia. 

Belladonna  and  Atr()i)ine,  332 

Lobelia,  312 

Nitrite  series,  395 

Iodides,  524 

Adrenaline,  372 

(Arsenic,  599) 

Pulmonary  disinfectanls.    (Seep.  130.) 

Creosote,  155 
Guaiacol,  155 
Tar,  155 

VI.  Drugs  used  for  their  effects  on  the 
central  nervous  system. 

i^timulants. 

(a)  The  spinal  cord. 
Strychnine,  275 

(b)  The  brain  and  niciliilla  ohlaii- 

(jala. 
.Atropine  (cocjiine),  360 
( "alTeine,  288 


Depressants. 

(a)  To  paralyze  sensation — Gen- 
eral aiuesthetics. 
Ether,      Chloroform,     Ethyl 
chloride,     Nitrous     oxide, 
220 
(6)   To   induce   sleep   and   rest — 
hypnotics  or  narcotics. 
Opium  and  Morphine,  252 
Alcohol,  188 
Chloral  gi'oup,  235 
Bromides,  265 
Hyoseine,  330 
Cannabis  indica,  260 
(c)   In  epilepsy. 

Bromides,  265 
(rf)  In  hysteria. 
Asafcrtida,  71 

For  surgical  operations. 

(a)  Ceneral  aiuesthetics. 
Chloroform,     Ether,     Ethyl- 
chloride,     Nitrous     oxide, 

220 

(b)  Morphine  and  hj-oscine,  252 

(c)  Cocaine  and   its  substitutes 

by  various  methods,  358 

(d)  Local  anaesthesia  by  cold,  70 

(e)  (Magnesium  sulphate  intra- 

spinallj^  568) 

To    relieve    pain — attalgcsics   or   ano- 
dynes. 

Opium,  252 
Cannabis,  260 
Antipyrine  series,  483 
(Alcohol,  188) 
(Chloral,  235) 

In  headache. 

Quinine,  467 
Antipyretics,  483 
Acetylsalicjdic  acid,  493 
Caff«>ine,  288 
Amyl  nitrite,  393 
Menthol  externally,  69 
(Arsenic,  loilides) 

In  cerebral  congestion. 

Nitrite  group,  394 

Purgatives  (croton  oil),  99 

Bleeding. 

Cold  to  the  head. 

//(  c('rclu-(d  anwniia. 

.\drenaline,  371 
i'ituitarv  extract,  384 
Digitalis  grouj),   115 

Vn.  Drugs  used  to  reduce  fever  tem- 
perature. 

Anlipyrine        and        .\ce(;uiilide 
group,  4S1 


i 


THERAPEUTIC  CLASSIFICATION 


691 


Cold  baths,  481 
Quinine,  467 
Aconite,  429 
Salicylic  acid  group,  493 

In  chills. 

Ipecacuanha,  440 
Opium,  252 

Quinine,  467 
Alcohol,  188 

Vin.  Drugs  used  for  their  effects  on  the 
liver. 

To    increase    the    secretion    of    bile^ 
cholagogues. 

Ox-gall,  115 
(Salicylic  acid,  493) 

IX.  Drugs  used  for  their  effects  on  the 
blood. 

To  increase  the  hcemoglohin. 

Iron,  645 

Arsenic,  600 

To  reduce  leucocytosis. 

Arsenic,  600 
Benzol,  503 
Quinine,  467 

To  increase  the  alkali. 

AlkaU  carbonate  group,  543 
Acetates  and  Citrates,  546 


X.  Drugs  used  for  specific  diseases. 

In  malaria. 

Quinine,  465 
Arsenic,  600 

In  syphilis. 

Mercury,  631 
Iodides,  523 
Arsenic,  600 
Salvarsan,  608 

In  diphtheria. 

Antidiphtheritic  serum,  496 

In  tetanus. 

Antitetanic  serum,  497 

Chloral,  235 

Bromides,  265 

(Magnesium  intraspinally,  568) 

In  cerebrospinal  meningitis. 

Antimeningococcus  serum,  497 


XI. 


In  amxhic  dysentery. 

Ipecacuanha,  440 
Emetine,  440 

In  rheumatic  fever. 
Salicylates,  491 

In  my.xcedema  and  some  other  thyroid 
diseases. 

Thyroid  extract,  532 
Iodides,  523 

hi  trypanosomiasis. 

Arsenic  (atoxyl),  604 
Antimony,  621 

In  gout. 

Colchicum,  443 
Atophan,  445 

In  obesity. 

Thyroid  extract,  532 
Saline  purgatives,  107 

In  chronic  rheumMism. 

Arsenic,  600 
Iodides,  523 
Alkalies,  542 

In  diseases  of  bone. 

{Rickets  and  Osteomalacia.) 
(Calcium,  561) 
Phosphorus,  585 
Arsenic,  599 

Drugs  used  for  their  effects  on  the 
skin. 

Corrosives  or  caustics,  Section  I. 
Emollients  and  protectives,  Section  I. 
Local  anodynes  and  anaesthetics,  Sec- 
tion I. 
Irritants. 

Turpentine  oil  group,  80 

Mustard,  82 

Cantharides,  83 

Camphor,  68 

Menthol,  69 

Iodine,  527 

Ammonia,  548 

Heat  and  cold,  79 

Carbonic  oxide  snow,  79 

Liniments,  685 

Disinfectant  or  irritant   ointments  in 
parasitic  skin  diseases. 

Mercury  ointment,  635 
Sulphur  ointment,  92 
Tar,  155 
Ichthyol,  156 

Benzoin,  Storax,  and  Peru  bal- 
sam, 501 


692 


THERAPEUTIC  CLASSIFICATION 


Naphthul,  151 

Resorcin,  155 

Pyrogallol,  152 

Chrj'sarobin,  153 

Camphor,  68 

Boracic  acid,  143 

Arsenic,  Iodide  of  Potassium,  etc., 

may  be  used  internally  in  skin 

diseases. 

Drugs  administered  internally  to  in- 
crease the  secretion  of  'perspira- 
tion (diaphoretics  or  sudorifics). 

Ipecacuanha,  439 

and  other  nauseating  expec- 
torants (antimony). 
Ipecacuanha  and  Opium  (Dover's 

powder),  439 
Camphor,  68 
Pilocarpine,  343 

Drugs  administered  internally  to  lessen 
secretion  of  perspiration. 

Atropine  and  Belladonna,  330 
Agaricin,  335 


Drugs  applied  locally  and  internally 
to  arrest  the  secretion  of  milk. 

(Atropine.) 

Xn,  Drugs  used  locally  for  their  effects 
on  the  eye. 

Astringents,  Section  I. 
Disinfectants,  Section  I. 
Caustics,  Section  I. 
Anodynes  and  ancesthetics,  Section  I. 

Drugs  dilating  the  pupil  and  relaxing 
the  accommodation — mydriatics. 

Atropine,     Homatropine,     Hyo- 

scine  and  Eumydrine,  331 
Cocaine,  358 
(Gelseminine,  303) 

Drugs  contracting  the  pupil  ajid  the 
ciliary  muscle — myotics. 

Physostigmine  or  Eserine,  349 
Pilocarpine,  344 


I 


INDEX. 


Abrin,  77,  499 
Abrus,  499 
Absinth,  58,  60,  60 
Acacia,  45 
Acaciae  gunimi,  45 
ACE  mixture,  219 
Aceta,  41 
Acetanilide,  470 
Acetanilidum,  480 
Acetates,  545 

of  ammonia,  294 
Acetic  acid,  555 
Acetophenone,  172 
Acetphenetidinum,  480 
Acctylatoxyl,  602 
Acetylcholine,  373 
Acetylsalicylic  acid,  486,  490 
Acids,  549 

acetic,  555 

acetylsalicylic,  486,  490 

benzoic,  161,  499 

boracic,  143 

boric,  143,  162 

caffeotannic,  455 

cambogic,  96 

camphoric,  335 

carbolic,  131 

carbonic,  571 

chromic,  143 

chrysophanic,  93,  153 

cinnamic,  500 

citric,  556 

cresotinic,  490 

digallic,  112  ' 

fihcic,  116 

flavaspidic,  116 

formic,  555 

gallic.  111 

gallotannic,  112 

hydrobromic,  265 

hydrochloric,  554 

li>^rocyanic,  449 

hjProfluoric,  566 

hydrosulphuric,  568,  569 

lactic,  556 

nitric,  554 

nitrohydrochloric,  555 

ophelic,  52 

osmic,  678 

oxalic,  556 

oxynaphtoic,  138 


Acids,  pannic,  116  (note) 

phosphoric,  555 

picric,  502 

piperinic,  54 

polygalic,  445 

prussic,  62,  449 

pyrogaUic,  153 

quillajac,  445 

quinic,  455,  545 

quinotannic,  455 

quinovatannic,  455 

quinovic,  455 

salicylic,  138 

sozoiodohc,  151 

sulphm'ic,  554 

tannic,  109 

tartaric,  556 

tropic,  314 
Acidum  acetylsalicylicum,  491 

arscniosum,  598 

benzoicum,  500 

chromicum,  675 

citricum,  556 

hydrocyanicum,  453 

salicylicum,  490 

tannicum,  112 

tartaricum,  556 
Acocanthera,  396,  397 
Acocantherin,  397 
Aconine,  425,  429 
Aconitine,  425 
Aconitum,  425 
Actol,  668 
Adeps,  47 

lanse,  47 
Adjuvants,  30  (note) 
Adnephrine,  370 
Adonis  vernalis,  396 
Adrenaline,  364 
Adrenine,  370  (note) 
^ther,  222 
^thyl  chloridum,  222 
Jilthyhs  carbamas,  234 

chloridum,  222 
Agar  agar,  107 
Agaricin,  335 
Agaricus,  335 

Age,  influence  of,  on  dose,  27 
Agropyrum,  46 
Agrostemma,  446 
Agurine,  288 
Airol,  671 
Albaspidin,  116 

( 693 ) 


G94 

Ahiohol,81,139,  172,  187 

amyl,  187 

Wtyl,  187 

chloroform  group,  IbU 

methyl,  186 

propyl,  187 

wood,  186 
Alkaloids,  36 
Alkasal,  673 
Allspice,  62 
AUyl-isosulphocyanate,  bJ: 

Almond,  48 

Almonds,  bitter,  62,  449 

sweet,  45 
Aloes,  93,  95 
Aloin,  93 
Aloinum,  95 
.\lsol,  673 
Althaea,  46 
Alum,  672 
Alumen,  673 
Aluminium,  672 
Alumnol,  673 
Alypine,  362 
American  hellebore,  4c5U 
Ammonia,  546 
Ammoniacum,  82 
Ammonii  benzoas,  oOl 
bromidum,  264 
carbonas,  548 
Ammonium,  301,  515 
acetate,  294 
benzoate,  191 
chloride,  518 
citrate,  294 
Amygdala  amara,  62 

dulcis,  45 
Amygdalin,  62,  449 
Amyl  alcohol,  187 
Amylene  hydrate,  23i 
Amylmorphine,  246 
Amylquinine,  301 
Amylum,  45 
Anacardium,  86 
Anacyclus,  54 
Anajsthesin,  363 
Anagallis,  56 
Analgcn,  470 
Andira  araroba,  lo6 
Anamirta,  277 
Anaphylaxis,  495 
Angostura  bark,  52 
Anhalonium,  257 
AniUne,  37,  470 
Anise,  62 
Antagonistics,  31 
Anthelmintics,  115 
Anthemis,  62 

Anthracene  purgatives,  JA 
Antliraquinone,  93 
Antiarin,  397 
Antiaris,  396 

Antidiphtheritic  serum,  49b 
Antifebriiio,  470,  480 
Antimcniiigitic  scrum,  497 
Antimunii  ct  potassu  tartras. 


INDEX 


621 


Antimoniuretted  hydrogen,  621 
1  Antimony,  618 

chloride  of,  621 
tartarated,  621 
Antinosine,  151 
Antipyretics,  470 
Antipyrina,  480 
Antipyrine,  470 
Antiseptics,  124 
Antitetanus  serum,  497 
Antitoxins,  494 

diphtheria,  496 
Antivenin,  498 
1  Apalache  tea,  280 
Aperients,  87,  90 
Apoatropine,  315 
Apocodeine,  435 
Apocynamarin,  397 
Apocynum,  396,  397,  414 
Apomorphine,  434 
Apple,  449,  504 
Aqua  regia,  555 
tofana,  587 
Aquae,  40 
Ai-abin,  45 
Arabinic  acid,  45 
Arbutin,  162,  291 
I  Arctostaphylos,  291 
Areca,  120 
Arecoline,  120,  336 
I  Argentamine,  668 
1  Aigenti  nitras,  667 
1  Argonin,  668 
1  Argyria,  666 
Arg^rol,  668 
Aricine,  455 
Aristochine,  465 
'  Aristol,  151 
Aristolochia,  52 
I  Armoracia,  B.  P.,  54,  bJ 
!  Arnica,  61,  80 
Aromatic  spirit  of  hartshorn,  54/ 
Arrhenal,  604 
Arsacetin,  602 
1  Arseni  iodidum,  599 
trioxidiim,  598 
1  Arsenic,  587  _ 

'  sulphur  compound?  oi,J>\)b 

Arseniuretted  hydrogen,  59» 
Arsenobenzol,  605 
Arsenophenylglycin,  bU^ 
Artemisia,  121 
Artemisin,  121 
Asafoctida,  71 
Asagraja,  430 
Aspidinin,  116 
Aspidinol,  116 
Aspidium,  116 
Aspidosamine,  454 
Aspidosperma,  454 
Aspidospcrmatme,  454 
Aspidospermine,  454 
I  Aspirin,  486,  490 
Assos'  milk,  50 
Astragalus,  45 
Atoiilian,  443 


m. 


Atro 
Atic 
AtK 


INDEX 


095 


Atoxyl,  G02,  604 
Atropa,  316,  329 

mandragora,  316 
Atropamine,  315 
AtropiniB  sulphas,  330 
Atropine,  314,  327 
Atroscine,  315 
Attar  of  roses,  62 
Aurantii  cortex,  62 


B 


Balsam,  38,  501 

of  copaiba,  78 

gurjun,  160 

of  Peru,  501 

of  Tolu,  501 
Balsamodendron,  82 
Balsamum  Peruvianum,  501 

tolutanum,  501 

traumaticum,  501 
Barbadoes  nuts,  96  (note) 
Barberry,  52 
Barbitonum,  234 
Barium,  396,  566 
Barley,  46,  291 
Barosma,  292 
Bases,  vegetable,  36 
Bebeerine,  52 
Beers,  188 

Belladonna,  316,  329 
Belladonnine,  315 
Benzaconine,  429 
Benzaldehyde,  62 
Benzaldehydum,  65 
Benzamina,  362 
Benzene,  503 
Benzoic  acid,  161,  499 
Benzoinum,  501 
Benzol,  503 
Benzosulphinidum,  50 
Benzoyl-ecgonine,  350,  357 
Benzjdmorphine,  246 
Berberine,  50,  385,  467 
Berberis,  52 
Bergamot,  63 
Beryllium,  515,  673  (note) 
Beta-eucaine,  362 
Beta-naphtol,  154 
Betel  nut,  336 
Betol,  157 
Betula,  486 
Bhang,  258 
Bicarbonates,  536 
Bile,  114 
Birch,  62,  486 
Bismuth,  669 
Bismuthi  subnitras,  670 
Bitter  almonds,  62,  449 
Bitters,  51 
Bittersweet,  446 
Black  draught,  95,  107 

nightshade,  446 

pepper,  54 

wash,  639 


Blaud's  pills,  648 
Blazing  star,  446 
Bleaching  powder,  167 
Blistering  collodion,  85 

liquid,  84 
Blood,  649 
Bloodroot,  257 
Blue  mass,  637 

ointment,  638 

pill,  637 
Blumea,  65 
Boletus,  335 
Bone  black,  571 
Boraeic  acid,  143 
Boral,  673 
Borax,  143 
Boric  acid,  143,  162 
Borneo-camphor,  65 
Borneol,  65 
Boroglycerin,  145 
Bougies,  33 
Brandy,  187 

Brassfounder's  ague,  662 
Brayera,  119 
Bromacetic  acid,  171 
Bromal,  233 
Bromated  camphor,  68 
Bromates,  147 
Bromeigon,  265 
Bromelin,  56 
Brometone,  233 
Bromide,  260 

ethyl,  220 

ethylene,  220 

of  potassium,  260 

of  sodium,  260 

of  strontium,  265 
Bromine,  166 
Bromipin,  265 
Bromism,  261 
Bromoform,  233 
Bromoformum,  234 
Bromural,  233 
Bromol,  135 
Broom,  303 

tops,  292 
Brown  mixture,  46,  249 
Brucine,  266,  275 
Buchu,  292 
Buckthorn,  95 

Burnett's  disinfecting  solution,  664 
Burnt  alum,  673 
Button-bush,  503 
Butyl  alcohol,  187 

chloral,  232 
Butyric  acid,  171 
Butyrates,  546 
Buxine,  51,  467 


Cacao,  280 
Cacao-butter,  290,  684 
Cachelot,  48 
Cachets,  42 


696 


INDEX 


Cactacete,  257 
Cacodylates,  604 
Cadmium,  67G 
Caesium,  515 
Caffeine,  280 
Caffeotannic  acid,  455 
Cajuput,  62 
Calabar  bean,  345 
Calabarine,  345 
Calcii  chloridum,  562 

hydras,  563 

lactas,  562 

sulphas  exsiccatus,  685 
Calcium  monosulphide,  570 

peroxide,  143 
Cali,  345 
Calomel,  637 
Calumha,  52 
Calumba)  radix,  52 
Calx,  563 

chlorinata,  167 

sulphurata,  570 
Cambogic  acid,  96 
Camphor,  58,  65,  277 

monobromated,  265 
Camphoric  acid,  335 
Camphorol,  68 
Canadian  hemp,  396,  414 
Canadine,  51,  385 
Cannabis  Indica,  258 
Canquoin's  paste,  664 
Cantharides,  292 
Cantharidin,  83 
Caprylates,  546 
Capsaicin,  54 
Capsicum,  54,  86,  465 
Capsules,  gelatin,  42 
Caraway,  62 
Carbo,  571 
Carbolic  acid,  131 
Carbonate,  536 

guaiacol,  162 
Carbonic  acid,  571 
Carbylamines,  450 
Cardamom,  62 
Cardol,  86 
Carlsbad  water,  106 
Carica,  56 
Carminatives,  59 
Carragheen,  46 
Carragheen  in,  46 
Carron  oil,  563 
Caruni,  62 
Caryojjhyllus,  62 
Casca  bark,  396 
Cascara,  93,  95 
Cassia,  95 
Cassiai  pulpa,  50 
Castile  soap,  684 
Castor  oil,  90,  498 
Cataplasiiia  kaolini,  684 
Cataplasmata,  42 
Catechu,  112 
Cathartics,  87 
CatharMii,  93 
Caustic,  lunar,  667 


Caustic  potash,  541 

toughened,  667 
Cayenne  pepper,  54 
Celandine,  257 
Cephajlis,  437 
Cephalathin,  503  (note) 
Cephalanthus,  503 
Cepha)line,  437 
Cera,  48 
Cerates,  33,  42 
Cerberin,  397 
Cerium,  678 
Cetaceum,  48 
Cetraria  islandica,  46 
Cevadilla,  430 
Cevadilline,  430 
Cevadine,  430 
Cevine,  430 
Chalybeate  pills,  648 
Chamtelirium,  446 
Chamomile,  62 
Charas,  258 
Charcoal,  570 
Charta,  42 
Chaulmoogra  oil,  86 
Cheiranthin,  397 
Chelerythrine,  257 
Chelidonine,  257 
Chelidonium,  257 

Chemical    constitution    and    pharmaco- 
logical action,  20 
Chemotherapy,  32  (note) 
Cherry,  449,  504 
ChiUies,  54 
Chimaphila,  292 
Chinaphenine,  465 
Chirata,  52 
Chiretta,  52 
Chloracetic  acid,  171 
Chloral,  228 

butyl,  232 

croton,  232 
Chloralamide,  232 
Chloralformamide,  232 
Chloralformamidum,  234 
Chloralose,  232 
Chlorates,  146 
Chlorcresols,  137 
Chloretone,  233,  234 
Chloride  of  antimony,  621 

ethyl,  219,  223,  226 

ferric,  647 

sodium,  505 
Chlorinated  lime,  167 

soda,  167 
Chlorine,  166 
Chlorodync,  250  (note) 
Chloroform,  69,  116,  139,  195,  222 
Chloroxylon,  86 
Chlorphonols,  135 
Chocolate,  280,  290 
Cholagogues,  87,  89 
Choline,  336 
I  Chondrodino,  52 
I  Chondrodendron,  52 
I  Chondrus,  46 


INDEX 


097 


Christmas  rose,  396 
Chromic  acid,  143 
Chromii  trioxidum,  675 
Chrysarobin,  153 
Chrj'sophanic  acid,  93,  153 
Churrus,  258 
Cicuta,  277 
Cicutoxin,  277 
Cinchona,  455,  463 
Cinchonamine,  455 
Cinchonidine,  455 
Cinchonine,  455 
Cineol,  121 
Cinnamic  acid,  500 
Cinnamon,  62 
Cinnamyl-cocaine,  350 
Citrates,  545 
Citric  acid,  556 
Citrine  ointment,  639 
Citrophen,  471 
Citrullus  colocynthis,  97 
Claviceps,  373 
Cloves,  62 
Club  moss,  49 
Cobalt,  676 
Cocaine,  350 

habit,  357 
Cocamine,  350,  357 
Coccus,  50 
Cochineal,  50 
Cochlearia,  54,  82 
Cocoa,  280 
Codamine,  236 
Codeine,  236,  246  (note) 
Cod-hver  oil,  681 
Coffee,  280,  289 
Coffeon,  289 
Cola,  280 
Colclaiceine,  440 
Colchicine,  440 
Colchicum,  442 
Cold  cream,  48 
Colica  pictonum,  653 

saturnina,  653 
Collargol,  668 
Collodia,  41,  685 
Collodion,  33 

blistering,  85 
Colloid  silver,  668 
Collodium  flexile,  685 
stypticum,  685 
vesicans,  685 
Colocynth,  96 
Colophony,  82 
Columbo,  52 
Commiphora,  82 

Concentration  of  drugs  in  tissues,  22 
Concusconine,  455 
Condurango,  52 
Confections,  41 
Conhydrine,  302 
Coniine,  302 " 
Conium,  302 
Conquairamidine,  455 
Conquairamine,  455 
Conquinamine,  455 


Conquinine,  455 

Convallaria,  396,  414 

Convolvulin,  96 

Convolvulus,  98 

Copaiba,  159,  292 
oil  of,  158 

Copaiva,  159 

Copper,  658 

Coriamyrtin,  277 

Coriander,  62 

Coriandrum,  62 

Coriaria,  277 

Cornsilk,  292 

Coronilla,  396 

Coronillin,  397 

Corrosive  sublimate,  139,  636 

Corynanthe,  363 

Cotarnine,  385 

Coto  bark,  52 

Cotton-seed  oil,  48 

Couch-gi-ass,  46 

Counter-irritation,  72 

Court  plaster,  685 

Creolin,  137 

Creosols,  137,  162 

Creosote,  162 

Cresalol,  157 

Cresol,  137 
Cresotinic  acid,  490 
Cresylic  acids,  137 
Creta,  564 
Crotin,  499 
Croton  chloral,  232 
oil,  73,  86,  96 
tiglium,  499 
Cryptopine,  236  (note),  247 
Cubeba,  160 
Cubebin,  158 
Cubebs,  158,  292 
Cuprea,  455 
Curara,  298 
Curarine,  298 
Curd  soap,  684 
Curine,  298 
Currier's  sumach,  277 
Cuscamidine,  455 
Cusamine,  455 
Cusconidine,  455 
Cusconine,  455 
Cusparia,  52 
Cusso,  118 
Cutol,  673 
Cyanogen,  450 
Cyclamin,  445 
Cylamen,  445 
Cynoctonine,  429 
Cynotoxin,  397 
Cytisine,  305 
Cytisus,  292,  305 
scoparius,  303 


Dandelion,  52 
Datm-a,  329 


098 


INDEX 


Datura  stramonium,  316 
Daturine,  315 
Dead  tongue,  277 
Deadly  nightshade,  316 
Death  camas,  430 
Decocta,  40 

Delirium  tremens,  192,  194 
Delphinine,  426 
Delphinium  staphisagria,  426 
Demulcents,  43 
Depression,  21 
Derivation,  72 
Dermol,  671 
Dextrins,  43 

Diacetylmorphine,  246,  249 
Diachylon,  47 

plaster,  685 
Diamorphinai  hydrochloridum,  250 
Diastase,  57 
Didymium,  515  (note) 
Diethylbarbituric  acid,  232 
Diethylendiamine,  545 
Digalen,  414 
Digalhc  acid,  112 
Digestive  ferments,  54 
Digipuratum,  414 
Digitalein,  396 
Digitalin,  396 
Digitahne,  414 
Digitaliresin,  277 
Digitalis,  395,  414 
Digitonin,  396,  446 
Digitoxin,  277,  396,  414 
Digitsaponin,  396 
Dill,  62 

oil  of,  65 
Dimethylethylcarbinol,  232 
Dimethylxanthine,  280 
Dionine,  246 

Diphtheria  antitoxin,  496 
Dipterocarpus  alatus,  160 
Discs,  41 

Disinfectants,  124 
Distribution  of  drugs  in  tissues,  22 
Diterpenes,  58 
Dithymol-diiodide,  151 
Diuretine,  288 

Donovan's  solution,  599,  637 
Dormiol,  233 
Dover's  powder,  249,  439 
Drastics,  87 
Drugs,  17 

administration  by  alimentary  tract, 
34 
influence  of  time  on,  28 
by  lungs,  34 
method  of,  32 
by  rectum,  36 
by  skin,  35 

cumulative  effects  of,  30 

elective  affinity  of,  23 

toh'rance  of,  29 
Dryobalanops,  65 
Dryopteris,  117 
Duboisia,  305 

myoporoides,  315 


Duboisine,  315 
Dusting  powders,  49 


Eau  de  cologne,  187 

Ecballium,  98 

Eccoprotics,  87 

Ecgonine,  314,  350,  357 

Eigon,  522 

Elseoptene,  58 

Elastica,  685 

Elaterium,  96,  98 

Elderflower,  62 

Elective  affinity  of  drugs,  23 

Elixirs,  40 

Embrocations,  41 

Emetine,  437 

Emodin,  93 

Emplastra,  32,  42 

Emplastrum  calefaciens,  84 

Emplastrum  adha;sivum,  685 

Emulsin,  45 

Emulsion,  34,  40,  62 

Enemata,  33,  42 

Epinephrine,  364 

Epinine,  371 

Epsom  salt,  101 

Erbium,  515  (note) 

Ergamine,  373 

Ergot,  373 

Ergotine,  373  (note) 

Ergotmine,  373 

Ernutine,  379 

Errhines,  33 

Erythrol  tetranitrate,  388,  393 

Erythrophlceine,  397 

Erythrophlocum,  396 

Erythrox-ylon,  358 

Eseramine,  345 

Eserine,  345,  348 

Essential  oils,  57 

Ethane,  171 

Ether,  69,  195,  222 

Ethereal  oil,  57 

Ethyl  bromide,  220 

carbamic  ester,  233 
chloride,  219,  223,  226 

Ethylene  bromide,  220 

Ethylhydrocupreine,  468 

Ethylmorphine,  246 

Eucalyptol,  58 

Eucalyptus,  62 
gum,  112 

Eudoxin,  671 

Eudoxine,  151 

Eugenol,  65 

Eumydrine,  328 

Euonyniin,  397 

Euonynuis,  9S,  414 

Euphorbia,  86 

Euphorbin,  86 

Euphorine,  471 

Euquinine,  465 

Europhen,  151 


4' 

1 


INDEX 


699 


Eurotium,  57 
Exalgine,  471 
Exodin,  95 
Exogonium,  97 
Extracts,  41 


Fel,  115 

Fennel,  62 

Ferments,  digestive,  54 

pancreatic,  55 
Ferratin,  649 
Ferri  chloridum,  647 
Ferric  chloride,  647 
Ferrocyanides,  450 
Ferruginous  pills,  648 
Ferrum  reductum,  648 
Ferula,  71 
Figs,  50,  56 
Filicic  acid,  116 
Filix  mas,  116 
Filmaron,  116 
Flavaspidic  acid,  116 
Flavaspidinin,  116 
Flowering  ash,  50 
Flowers  of  benzoin,  500 

of  sulphur,  92 
Fluid  extracts,  41 
Fluidex-tracta,  41 
Fluidextractum  aromaticum,  04 
Fluorides,  565 
Foeniculum,  62 
Formaldehyde,  163 
Formalin,  164 
Formates,  546 
Formic  acid,  555 
Fowler's  solution,  598 
Foxglove,  396,  414 
Frangula,  93,  95 
Frangulin,  93 
Friar's  balsam,  501 
Fuller's  earth,  49 
Furfurol,  187 
Fusel  oil,  187 


G 


Gadus  morrhua,  681 
Galbanum,  82 
GaUa,  112 
GaUic  acid,  111 
Gallol,  673 

Gallotannic  acid,  102,  112 
Gambir,  112 
Gamboge,  98 
Ganja,  258 
Garcia,  96  (note) 
Gargarisma,  33 
Gaultheria,  486 
Gelsemine,  266 
Gelsemium,  303 
General  action,  24 

anaesthetics,  195 
Genito-urinary  antiseptics,  158 


Gentian,  52 

Gin,  187 

Ginger,  62 

Gitalin,  396 

Gitin,  396 

Glandulse  thyroidese,  532 

Glauber's  salt,  101 

Glucose,  50 

Glucosides,  38 

Glusidum,  50 

Glycerin,  92,  171 

Glycerina,  41 

Glycerinum,  48 

Glycerita,  41 

Glycero-phosphates,  108,  684 

Glycerylis  nitratis,  393 

Glycosides,  38 

Glycyrrhiza,  45 

Glycyrrhizin,  45 

Gnoscopine,  236  (note) 

Goa  powder,  153 

Gold,  673 

Golden  seal,  385 

Gonosan,  160 

Gorit,  143 

Gorse,  305 

Goulard's  extract,  657 

lotion,  657 
Granatum,  119 
Gray  oil,  638 

powder,  637 
Green  hellebore,  430 
Griffith's  mixtm-e,  648 
Groundsel,  503 
Guaiacol,  162 

carbonate,  162 
Guaiacolsalol,  157 
Guaiacum,  82 
Guarana,  280 
Gum,  38,  43 

arable,  45 
Gum-resins,  38 
Gurjun  balsam,  160 
Gymnemic  acid,  354 
Gypsophila-sapotoxin,  446 
Gypsum,  683 


H^MATOXYLON,  112 

Haemoglobin,  649 

Hagenia,  119 

Hamamelis,  112 

Harmine,  467 

Hartshorn,  aromatic  spirit  of,  547 

Hashish,  258 

Heavy  metals,  611 

Hedonal,  233,  234 

Hellebore,  American,  430 

green,  430 

white,  430 
Helleborein,  397 
Helleborus,  396 
Hemisine,  370 
Hemlock,  302 


700 


INDEX 


Hemostasine,  370 
Henbane,  316,  329 
Hcpar  sulphuris,  570 
Heroine,  246,  249 
Hespcridin,  64 
Hcxamethylenamine,  161 
Hexamethylentctramine,  160 
Hexaniine,  161 
Histamine,  373 
Hoffmann's  anodyne,  70 
Holocaine,  363 
Homatropine,  315,  328 
Homochelidoninc,  257 
Homocinchonidinc,  455 
Homococamine,  350 
Homoisococamnic,  350 
Honey,  50 
Hops,  52 
Hordeum,  46 
Horehound,  62 
Horseradish,  54,  82 
Humulus,  52 

Hmiyadi-Janos  water,  106 
Hydragogues,  87 
Iiydrarg3Ti  chloridum,  636 

iodidum,  636 
Hydrargyrum  cum  creta,  637 
Hydrastine,  385 
Hydrastinine,  385 
Hydrastis,  385 
Hydrates,  536 
Hydrobromic  acid,  265 
Hydrochloric  acid,  554 
Hydrocinchonine,  455 
Hydrocotarnine,  236  (note),  247 
Hydrocyanic  acid,  449 
Hydrofluoric  acid,  566 
Hydrogen  arseniuretted,  598 
dioxide,  141 
ion,  549 
peroxide,  140 
phosphuretted,  585 
sulphide,  569 
Hydroquinidine,  455 
Hydrotjuinine,  455 
Hydroquinone,  155.,  291 
Hydrosulphuric  acid,  568,  569 
Hydroxyl  ion,  536 
Hydroxyphenylethylamine,  373 
Hyoscine,  314,  327,  330 
Hyoscyaminc,  314,  327,  330 
Hyoscyamus,  316,  329 
Hypertonic  solution,  26 
Hypnone,  233 
Hypochlorite,  167 
Hypodermic  medication,  35 
Hypophospliites,  684 
Hypophysin,  384 
Hypoquebrachine,  454 
Hypotonic  solution,  20 
Hyrgol,  639 


IcKi.AND  moss,  46 
I(!hthyol,  156 


Idiosyncrasies,  29 
Ignatia,  266,  494 
Ilex,  280 
Immunity,  29 
Indian  hemp,  258,  260 

tobacco,  305 
Indirect  action,  24 
Infundibulin,  384 
Infusa,  40 
Ingluvin,  56 
Inhalation,  34 
Intestinal  disinfectants,  157 
Intravenous  anaesthesia,  218 

injections,  36 
lodalbumin,  532 
lodates,  147 
Iodide,  518 
Iodine,  149,  525 
lodipin,  522 
lodism,  519 
Iodoform,  149 
lodol,  151 
lodolen,  522 
lodolum,  151 
lodospongin,  532 
lodothyrin,  528 
ledum,  527 
Ions,  26 

Ipecacuanha,  437 
Ipomcea,  97 
Irish  moss,  46 
Iron,  640 
Irritation,  21 
Isinglass,  685 
Isoamylamine,  373 
Isococamine,  350 
Isonitriles,  450 
Isophysostigmine,  345 
Isopilocarpine,  336 
Isopral,  233,  234 
Isopunicine,  119 
Isoquinoline,  37,  303 
Isotonic  solution,  26 
Itrol,  668 


Jaborandi,  336 
Jaborine,  336  (note) 
Jalap,  96 
Japaconine,  426 
Japaconitine,  425 
Jasmine,  303 
Jateorrhiza,  52 
Jatropha,  96  (note) 
Javelle's  solution,  167 
Jequirity,  499 
Jervine,  430 
Jesuit's  drops,  501 
Juniper,  62,  80 


Kairinr,  470 
Kairoliue,  470 


INDEX 


701 


Kali,  345 
Kamala,  120 
Kaolin,  49 
Kaolinum,  684 
Kava  Kava,  54 
Keratin,  684 
Kino,  112 

eucalypti,  112 
Kola,  280 
Kosotoxin,  118 
Koiisso,  118 
Krameria,  112 
Krj'ofine,  471 


Labarraque's  solution,  167 

Laburnum,  305 

Lactates,  546 

Lactation  in  reference  to  dose,  28 

Lactic  acid,  556 

Lactophenine,  480 

Lactose,  50 

Lsevohyoscyamine,  315 

Lambkin's  cream  638 

Lamella;,  33,  41 

Lanolin,  47 

Lanthanum,  515  (note) 

Lanthopine,  236,  (note) 

Lappaconitine,  429 

Lard,  47 

Largin,  668 

Laudanine,  236  (note),  247 

Laudanosine,  236  (note) 

Laudanum,  249 

Laughing  gas,  224 

Laurel,  449 

leaves,  62 
Lavender,  62 
Laxatives,  87 
Lead,  650,  685 

sugar  of,  656 
Lemon-peel,  62 
Lemonades,  556 
Levico  water,  598 
Lily  of  the  valley,  396,  414 
Lime,  chlorinated,  167 

slaked,  563 

sulphm'ated,  570 

unslaked,  563 
Limonis  cortex,  62 
Liniments,  41,  685 
Linseed,  46 
Linum,  46 
Lipanin,  682 
Liqueurs,  187 
Liquid  petrolate,  107 
Liquor  antisepticus,  145 

arseni  et  hydrargj^ri  iodidi,  637 

arsenicalis,  598 

chlori,  167 

epispasticus,  84 

sodse  chlorinata;,  167 
^  trinitrini,  393 
Liquidambav,  501 


Liquid  extracts,  41 

Liquorice  root,  45 

Lithii  carbonas,  542 

Lithium,  515 

Liver  of  sulphur,  570 

Lobelia,  305 

Lobeline,  305 

Local  action,  24 

Logwood,  112 

Loretin,  151 

Losophan,  151 

Lotions,  40 

Lozenges,  33,  41 

Lugol's  solution,  527 

Lunar  caustic,  667 

Lungs,  administration  of  drugs  by,  34 

Lupines,  303 

Lupulin,  52 

Lycaconitine,  429 

Lycetol,  545 

Lycopodium,  49 

Lysidine,  545 

Lysol,  137 

Lytta,  83 


M 

Mace  oil,  63 

Magisterium  bismuthi,  670 
Magnesia,  106,  542 
Magnesii  carbonas,  106,  542 

citras,  106 

oxydum,  106,  542 

sulphas,  105,  106 
Magnesium,  566 

carbonate,  101 

peroxide,  143 

sulphate,  101 
Malakine,  471,  480 
Male  fern,  116 
Mallotoxin,  120 
Mallotus,  120 
Malonates,  566 
Malt,  50,  57 
Maltum,  50 
Maltzyme,  57 
Mandragora,  315 
Mandragorine,  315 
Mandrake,  315,  316 
Manganate,  676 
Manganese,  676 
Manicheel,  86 
Manna,  50 

Mannitol  hexanitrate,  388 
Marrubium,  62 
Marsdenia,  52 
MarshmaUow,  46 
Massa,  41 

hydrargyri,  637 
Masses,  41 
Materia  medica,  18 
Matico,  160 
Matricaria,  62 
Meconidine,  236  (note) 
Medinal,  232 


702 


INDEX 


Mel,  56 

Menispermine,  51 

Menispermum,  277 

Menstruation,  influence  of,  on  dose,  28 

Mentha,  62 

Menthol,  65 

Mercuriahsm,  622 

Mercuric  perchloride,  139 

Mercury,  622 

with  chalk,  637 
Mesotan,  493 
Metadiuitrobenzol,  502 
Metaoxybenzoic  acid,  490 
Mctaphosphates,  105 
Methane  scries,  169 
Methyl  alcohol,  186 
Methylamine,  517 
Methylarbutin,  291 
Methylatropine,  328 
Methylconiine,  302 
Methylhordenine,  305 
Methylis  salicylas,  491 
Methylsalicylate,  486,  489 
Methylstrychnine,  301 
Methylsulphonal,  234 
Meyer-Overton  theory,  169 

Mezcal,  257 
MezcaUne,  257 

Mezereum,  86 
Milk  of  lime,  563 
of  sulphur,  92 
sugar  of,  50 
Mistura  glycyrrhizte,  249 

MisturiB,  40 

Mithridatism,  29 

Mixtures,  40 

Molybdenum,  677 

Monk's-hood,  429 

Monobromated  camphor,  265 

Monsel's  solution,  648 

Morpliine,  236 

Muawine,  397 

Mucilages,  40 

Mucuna,  345 

Muscale,  257 

Muscarine,  336 

Mustard,  54,  82 
leaf,  83 

Mutton  suet,  48 

Mylabis,  84 

Myoctonine,  429 

Myriapoda,  449 

Myristica,  62 

Myristicin,  58,  60 

Myrosin,  82 

Myroxylon,  501 

Myrrh  a,  82 


N 


Naphtiialin,  154 
Naphthalol,  157 
Naplithol,  154 
Naphtliol,  116 
Narceine,  236  (note),  247 


Narcophine,  248 
Narcotics,  169 

of  methane  series,  127 
Narcotine,  236,  247,  385 
Nectandra,  52 
Neosalvarsan,  603 
Neriin,  397 
Neriodorin,  397 
Nerium,  396 
Neuronal,  233 
Ngai-camphor,  65 
Nickel,  676 
Nicotiana,  304 
Nicotine,  304 
Nirvaine,  363 
Nitrate,  293 
Nitre,  294 
Nitric  acid,  554 

esters,  387 
Nitriles,  450 
Nitrite,  387 

of  amyl,  387  . 

of  sodium,  387 
Nitrobenzol  compounds,  502 
Nitro-bodies,  388 
Nitroethane,  388 
Nitroglycerin,  387 
Nitrohydrochloric  acid,  555 
Nitromethane,  388 
Nitrous  esters,  387 

oxide,  224 
Nosophen,  151 
Novatophan,  444 
Novocaine,  362 
Nut-gall,  112 
Nutmeg,  60,  62  ^ 
Nux  vomica,  266 


(Enanthe,  277 

GEnanthic  ethers,  172,  187 

(Enanthotoxin,  277 

(Enanthylates,  546 

Oil  of  copaiba,  158 
volatile,  57 

Ointment,  32,  41,  47 
blue,  638 
citrine,  639 

Olea  europira,  48 

Oleander,  396 

Oleandresin,  277 

Oleandrin,  277 

Oleata,  33 

Oleoresins,  38 

Oleum  amygdalae,  48 
expressum,  48 
anethi,  62 
betula^,  62,  491 
cajuputi,  62 
cinereum,  638 
gaulthcria;,  62,  491 
gossypii  sominis,  48 
licdt'onue,  t)2 
jecoris  aselli,  682 


i 


INDEX 


703 


Oleum  junipcri,  62,  SO 

lavandulse,  62 

menthse,  62 

morrhuae,  682 

olivsB,  48 

phosphoratuni,  585 

picis  liquida3,  156 

ricini,  90 

rosac,  62 

rosmarini,  62 

santali,  160 

sinapis,  83 

terebinthinse,  86 

theobromatis,  684 

thymi,  62 

tiglii,  97 
Olive,  48 
Oninopon,  248 
Omphalea,  96  (note) 
Ophclic  acid,  52 
Opium,  236,  248 
Orange  peel,  62 
Ordeal  bean,  345 
Organic  acids,  555 

extracts,  384 
Organotherapy,  384 
Organotropic,  125  (note) 
Ori)hol,  671 
Orpiment,  587 
Orthoform,  363 
Oscine,  315 
Osmic  acid,  678 
Otto  of  roses,  62 
Ouabain,  397 
Ouabaio,  396 
Ourouparia,  112 
Ovaries,  385 
Oxalates,  565 
Oxalic  acid,  556 
Oxazine,  37 
Oxydimorphine,  246 
Oxygen,  574 
Oxynaphtoic  acids,  138 
Oxynarcotine,  236  (note) 
Ozone,  575 


Painter's  colic,  653 

I?alsy,  653 
Palmitine,  52 
Panama  bark,  448 
Pancreatic  ferments,  55 
Pancreatin,  55 
Pannic  acid,  116  (note) 
Pantopon,  248 
Papain,  56 
Papaver,  236 
Papaveramine,  236  (note) 
Papaverine,  236,  247 
Papayotin,  56 
Papoid,  56 
Paraffins,  48,  107 
Paraform,  164 
Paraguay  tea,  280 


Paraldehyde,  231 
Paralysis,  21 

saturnina,  653 
Paramidophcnol,  471 
Paraoxybenzoic  acid,  490 
Paraphcnolsulphonates,  138 
Parasitotropic,  125  (note) 
Paregoric,  168,  249 
Pareira,  52 
Parillin,  446 
Paris  green,  587 
Pathology,    relation     to    pharmacology, 

17 
Paulinia,  280 
Pawpaw,  56 
Payta,  454 
Paytanine,  454 
Paytine,  454 
Pear,  504 

Pearson's  solution,  599 
Peganum,  467 
Pelletierine,  119 
PeUitory,  54 
Pellote,  257 
PeUotine,  257 
Pennyroyal,  59 
Pental,  220 
Pepper,  53 

black,  54 

cayenne,  54 
Peppers,  160 
Peppermint,  61 
Pepsin,  55 
Perchlorates,  147 
Perchlorethane,  220 
Permanganate  of  potassium,  676 
Peronine,  246 
Peroxide  of  calcium,  143 

of  hydrogen,  140 
Persodine,  143 
Persulphates,  143 
Petrolates,  48 
Peyotl,  257 
Pharmacognosy,  18 
Pharmacology,  definition  of,  17 
Pharmacopoeias,  39 
Pharmacy,  18 
Phenacetine,  471 
Phenacetinum,  480 
Phenazonum,  480 
Phenetidines,  471 
Phenocoll,  471,  480 
Phenol,  131 

hquefactum,  135 
Phenylhydrazine,  470 
Phenolphthalein,  91 
Phenylquinohne  carbonic  acid,  443 
Phenyl  salicylate,  157,  486 
Phloretin,  505 
Phloridzin,  504 
Phosphate,  105 

of  sodium,  101 
Phosphoric  acid,  555 
Phosphorus,  576 
Phosphuretted  hydrogen,  585 
Physeter,  48 


704 


INDEX 


Physiology,  rclaUoii  to  pliannacolugy, 

PhysostigiiKX,  345 

Physostigmiue,  100,  345 

Physovenine,  345 

PicriEna,  52 

Picric  acid,  502 

Picropodophyllin,  96 

Picrotin,  277 

Picrotoxin,  277 

Pills,  41 

Blaud's,  G48 

blue,  637 

chalybeate,  648 

ferruginous,  648 

Plummer's,  621 
Pilocarpidine,  336  (note) 
Pilocarpine,  336 
Pilocarpus,  336 
Pilula,41 

hydrargyri,  637 

ipecacuanhas  cum  scilla,  414 

plumbi  cum  opio,  250 

saponis  composita,  250 
Pimenta,  62 
Pimpernel,  56 
Pimpinella,  62 
Pine-apple,  66 
Pink  root,  123 
Pinus,  80, 156 
Piper,  54 

cubeba, 160 
Piperazine,  545 
Piperidine,  54 
Piperine,  54, 465 
Piperinicacid,54 
Pipsissewa,  292 
Pituglandol,  384 
Pituitary  extract,  381 
Pituitrin,  384 
Pituri,  305 
Pixliquida,  156 
Plasters,  32,  42,  685 

diachylon,  685 

warming,  84 
Platinum,  673 
Plum,  449,  504 
Plumbi  acetas,  656 
Plummer's  pills,  621 
Poison,  17 

ivy,  85 

oak,  85 

protoplasm,  23 
Polygala,  448 

senega,  445 
Polygalic  acid,  445 
Pomegranate,  109 
Poplars,  486 
Poppy,  236 
Porcelain  clay,  684 
Potassa  caustica,  541 

cum  calce,  563 

sulphurata,  570 
Potassii  acetas,  54(5 

bicarbonas,  541 

biciu'oinas,  675 

bitartras,  106 


17    Pot:i.*-sii  carbonas,  541 

citras,  546 

dichromas,  675 

hydroxidum,  541 

iodidum,  522 

nitras,  294 

permanganas,  143 

et  sodii  tartras,  106 

tartras,  106 
Potassium,  513 

arsenite,  598 

bromide,  260 

chlorate,  145 
.  hydrate,  551 

myronate,  82 

permanganate,  676 
Potato,  446 

leaves,  316 
Poultices,  42 
Powders,  41 

dusting,  29 

gray,  637 
Pregnancy,  influence  of,  on  dose,  28 
Primula  obconica,  86 
Propionates,  546 
Proponal,  234 
Propyl  alcohol,  187 
Protargol,  668 
Protocurarine,  298 
Protopine,  236  (note),  247,  257 
Protoplasm  poisons,  23 
Protoveratridine,  430 
Protoveratrine,  430 
Prunes,  50,  62,  449 
Prunus,  45 

Prunus  Virginiana,  62 
Prussic  acid,  62,  449 
Pseudaconine,  426 
Pseudaconitine,  425 
Pseudo-hyoscyaminc,  315 
Pseudojervine,  430 
Pseudo-morphine,  236  (note) 
Psychoria,  439 
Psychotrine,  437 
Pterocarpus,  112 
Pulegon,  60 
Pulveres,  41 
Pulvis  aromaticus,  64 

cretas  aromaticus  cum  opio,  249 

effervescens,  106 

ipecacuanha;  compositus,  249 
et  opii,  249 

kino  compositus,  249 

soda;  tartarata;,  106 
Punica,  119 
Punicine,  119 
Purgatin,  95 
Purgatives,  87 
Purging  cassia,  50 

nuts,  96  (note) 
Pustulants,  72 
Pyramidon,  470,  480 
Pyretlirum,  54 
Pyridine,  37,  302 
Pyrocatechin,  155 
Pyrogallic  acid,  153 


I 


INDEX 


705 


Pyrogallol,  152 
Pyrophosphates,  105 
Pyrrol,  37 


QUAIRAMIDINE,  455 

Quau-amine,  455 
Quassia,  52,  116 
Quebrachamine,  454 
Quebrachine,  454 
Quebracho,  454 
Quillaja,  445 
Quillajac  acid,  445 
Quinamine,  455 
Quince  seeds,  46 
Quinic  acid,  455,  545 
Quinidine,  455 
Quinine,  455 
Quinohne,  37,  470 
Quinotannic  acid,  455 
Quinova-red,  455 
Quinovatannic  acid,  455 
Quinovic  acid,  455 
Quinovin,  455 


Racemic  narcotine,  236  (note) 

Ragwort,  503 

Ratsbane,  598 

Realgar,  587 

Rectified  spirit,  187 

Rectum,  administration  of  drugs  by,  36 

Remijia,  455 

Remote  action,  24 

Resin,  38,  82 

Resina,  82 

Resorcin,  155 

Resorcinol,  155 

Revulsion,  72 

Rhamnus,  95 

Rhatany,  112 

Rheum,  94 

Rhoeadine,  236  (note) 

Rhubarb,  93,  94 

Rhus  toxicodendron,  85 

Ricin,  498 

Ricinus,  91,  498 

Rochelle  salt,  101 

Rosa,  62 

Rosemary,  62 

Rottlerin,  120 

Rubefacients,  72 

Rubidium,  515 

Rubijervine,  430 

Rum,  187 


Sabadinb,  430 
Sabadinine,  430 
Sabatrino,  430 
Sabinol,  58 
Sabromine,  265 
45 


Saccliarides,  38 
Saccharin,  50 
Saccharum,  49 

lactis,  50 
Saffron,  50 
Safrol,  58,  60 
Safrolum,  64 
Sage,  59,  60,  62 
Sajodin,  522 
Sal  volatile,  547 
Salep,  46 
Salicin,  486,  490 
Salicylate,  485 

of /3-naphtol,  157 

of  cresol,  157 

of  sodium,  138,  486 
Salicylates,  161,  485 
SalicyUc  acid,  138,  485 
Saline  diuretics,  292 
Sahpyrine,  470 
Saliva,  62 
SalocoU,  471,  480 
Salol,  157,  486 
Salophen,  471,  480 
Salt-action,  25 

of  lemon,  556 

of  sorrel,  556 
Saltpetre^  294 
Salumin,  673 
Salvarsan,  603 
Salves,  32,  41 
Samandarine,  277 
Sandalwood,  oil  of,  158 
Sanguinaria,  257 
Sanguinarine,  257 
Santalol,  158 
Santalum,  160 
Santonin,  121 
Santyl,  160 
Sapo,  684 

viridis,  684 
Saponaria,  445 
Saponin,  445 
Sapotoxin,  445 
SarsapariUa,  446,  448 
Sassafras,  46,  62 
Sassy  bark,  396 
Satinwood,  86 
Savine,  58,  60 
Scammony,  98 
Scheele's  green,  587 
Schweinfiu-t's  green,  587 
Scilla,  396,  414 
Scoparin,  292 
Scoparius,  292 
Scopola,  329 

atropoides,  316 
Scopolamine,  314,  327,  330 
Scopoleines,  315,  329 
Scopoline,  315 
Scotch  paregoric,  249  (note) 
Scurvy  grass,  54 
Secale,  373 
Selenium,  677 
Semecarpus,  86 
Senecio,  503 


706 


INDEX 


Senega,  448 

Senegin,  445 

Senna,  93 

Septcntrionalinc,  429 

Serpentaria,  52 

Serum,  antidiphthoricum,  496 

antitetanus,  497 
Sesquiterpenes,  58 
Sevum,  48 

Sex,  influence  of,  on  dose,  28 
Shccnocaulon,  430 
Silver,  664 

nitrate,  139 
Sinalbin,  82 
Sinapine,  82 
Sinapis,  82 
Sinigrin,  82 

Size,  influence  of,  on  dose,  27 
Slaked  lime,  563 
Slippery  elrn,  46 
Smelling  salts,  548 
Smilacin,  446 
Smilax,  446 
Snake-root,  52 
Snuff,  33 
Soamine,  603 
Soap,  684 

castile,  684 

curd,  684 
Soapbark,  445 
Soapwort,  445 
Sodii  arsenas,  598 

benzoas,  501 

bicarbonas,  542 

boras,  145 

carbonas,  541 

hydroxidum,  541 

phenolsulphonas,  138 

phosphas,  105,  106 
acidus,  555 

et  potassii  tartras,  106 

salicylas,  490 

sulphas,  105,  106 

sulphis,  535 

thiosulphas,  535 
Sodium  arsanilatc,  602 

bromide,  260 

cacodylato,  604 

chloride,  505 

fluorosilicate,  566 

nitrite  of,  387 

phosphate,  101 

saUcylate,  138,  486 

tartrate,  101 
Solanacea;,  314 
Solanidine,  446 
Solanine,  445 
Solanum,  446 
Solutol,  137 
Solveol,  137 
Soporifics,  228 
Sowbread,  445 
Sozoiodolate,  151 
Sozoiodolic  acid,  151 
Spanish  fly,  83 
Sparteine,  303 


Spartium,  303 
Spearmint,  61 
Spermaceti,  48 
Spigelia,  123 
Spirits,  40,  172,  187 

of  hartshorn,  aromatic   547 
Spiritus  aetheris  nitrosi,  393 

frumenti,  187 

rectificatus,  187 

vini  galliei,  187 
SquiUs,  396,  414 
Squirting  cucumber.  98 
Starch,  45,  49 
Stavesacre,  426 
Stearoptene,  58 
Sterculia,  280 
Sternutatories,  33 
Stibine,  621 
Stimulation,  21 
Storax,  501 
Stovaine,  362 
Stramonium,  329 
Strontium,  566 

bromide,  265 
Strophanthin,  397 
Strophanthinum,  414 
Strophanthus,  396,  414 
Strychnine,  266 
Strychnos,  266,  298 
Stypticine,  386 
Styptol,  386 
Styrax,  501 

Subcutaneous  injection,  35 
Subcutine,  363 
Substituted  ammonias,  517 
Succinates,  566 
Suet,  48 
Sugar  of  lead,  656 

of  milk,  50 
Sugars,  49 
Sulphate,  105 

of  magnesium,  101 
Sulphides,  92,  568,  570 
Sulphites,  535 
Sulphocarbolates,  138 
Sulphonal,  231 
Sulphonethylmethanum,  234 
Sulphonmethanum,  234 
Sulphur,  92,  568 

compounds  of  arsenic,  598 

dioxide,  165 

flowers  of,  92 

liver  of,  570 

milk  of,  92 
Sulphurated  lime,  570 
Sulphuretted  hydrogen,  569 
Sulphuric  acid,  554 
Sumbul,  71 

Suppositoria  plumbi  composita,  250 
Suppositories,  33,  41 
Supracapsuline,  370 
Suprarenaline,  370  (note) 
Suprarenine,  364,  371 
Swamp  dogwood,  503 
Sweet  almonds,  45 
Swcrtia,  52 


INDEX 


707 


Synergists,  30 
Syrups,  40 
Syrupus,  49 

aromaticus,  64 


Tabell/e,  41 

Tablet  triturates,  42 

Tablets,  41 

Tablett£e,  42 

Taka-diastase,  57 

Taki,  49 

Tamarinds,  50 

Tanghiuin,  397 

Tannal,  673 

Tannalbin,  112 

Tannate,  639 

Tannic  acid,  109 

Tannigen,  112 

Tannin,  109 

Tannocol,  112 

Tannoform,  112 

Tannopin,  112 

Tansy,  59,  116 

Tar,  155 

Taraktogcnos,  80 

Taraxacum,  52 

Tartar  emetic,  73,  618 

Tartarated  antimony,  621 

Tartaric  acid,  556 

Tartrate,  105 

Tea,  280,  289 

Tellurium,  677 

Terebenum,  80 

Terebinthina,  80 

Terpenes,  57 

Terpini  hydras,  80 

Tetrachloride  of  carbon,  220 

Tetrachlorphenolphthalein,  91,  100 

Tetrahydronaphthjdamino,  485 

Tetraiodpyrrol,  151 

Tetronal,  231,  234 

ThalHne,  470 

Thallium,  677 

Thea,  280 

Thebaine,  236,  247,  266 

Theobroma,  280,  684 

Theobromine,  280 

Theocine,280,  288    " 

Theon,  290 

Theophylline,  280 

Therapeutics,  definition,  17 

Thermodine,  471,  480 

Thevetia,  396 

Thevetin,  397 

Thioform,  671 

Thiosulphate,  535 

Thorium,  678 

Thornapple,  316 

Thujon,  58,  66,  277 

Thyiue,  ()2 

oil  of,  62 
Thymol,  58,  120,  138 
Tlivinolis  iodidum,  151 


Thj'-mosalol,  157 

Thyreoglobulin,  528 

Thyroid  gland,  527 

Thyroideum  siccum,  532 

Thyroidin,  528 

Tin,  677 

Tinctura  camphorse,  249 

Tinctures,  40 

Toads,  396 

Tobacco,  304,  312,  316 

Tolerance  of  drugs,  29 

Toluifera  Pereira,  501 

Toluylendiamine,  503 

Toot,  277 

Toughened  caustic;,  667 

Toxicodendrol,  85 

Toxicology,  17 

Toxins,  494 

Toxiresin,  277 

Tragacantha,  45 

Tragacanthin,  45 

Triln-omphenol,  135 

Trichlorhydrin,  171 

Trichlorisopropylalcohol,  233 

Trichlorpseudobutylalcohol,  23C 

Triiodocresol,  151 

Trimethylamine,  171 

Trimethylammonium,  518 

Trimethylethylene,  220 

Trimethylxanthine,  280 

Trinitrin,  393 

Trional,  231,  234 

Triticum,  46 

Tritopine,  236  (note) 

Tritiu-ations,  41 

Troches,  41 

Trochisci,  33,  41 

Tropeines,  315 

Tropic  acid,  314 

Tropine,  314,  329 

Tropacocaine,  350,  302 

Tubocurarin  e,  298 

Tungsten,  677 

Turlingston's  balsam,  501 

Tm-pentine,  116 

oil  of,  60,  SO,  139 
Tutin,  277 
Tutu,  277 
Tyramine,  373 

U 

Ulmus,  46 
Uncaria,  112 
Uncomocomo,  116  (note) 
Unguenta,  32,  41 
Unguentum,  47 

aquae  rosae,  48 

hydrargyri,  638 
Unslaked  lime,  563 
Upas  tree,  396 
Uranium,  677 
Urari,  298 
Urea,  294 
Urechites,  396 
Urcthane,  233 


708 


INDEX 


Urginea  raaritima,  414 
Urotropine,  160 
Uva  Ursi,  162,  291 


Valerian,  71 
Valerianates,  546 
Vanadium,  677 
Vanilla,  62 
Vanillin,  58,  65 
Vaselin,  48 

Vasoconstrictino,  370  (note) 
Veratridine,  430 
Veratrine,  430 
Verbascum,  46 
Veronal,  232 
Veratrum,  430 
Vermicides,  115 
Vermifuges,  115 
Vesicants,  72 
Vienna  paste,  563 
Vinegar,  555 

medicated,  41 
Vinum  antimoniale,  021 

antimonii,  621 
Vioform,  151 
Virginian  cherry,  450 

prune,  62 
Volatile  liniment,  548 


W 

Wahoo,  98,  414 
Warburg's  tincture,  465 
Warming  plaster,  84 
Water,  505 

dropwort,  277 


Water,  medicated,  40 
Wax,  48,  685 

Weight,  influence  of,  on  dose  2  7 
Whiskey,  187 
White  agaric,  335 
hellebore,  430 
Willows,  486 
Wines,  188 
Wintergreen,  62,  486 
Witchhazel,  112 
Wood  alcohol,  180 
Wool-fat,  47 
Woorali,  298 
Woorara,  298 
Wormwood,  60,  66 


Xanthine,  280 
Xeroform,  071 


Yellow  wash,  639 
Yerba  Mate,  280 
Yohimbine,  363 
Young's  formula,  28 
Youpon,  280 
Yttrium,  515  (note) 


Zea,  292 
Zinc,  662 

peroxide,  143 
Zinci  sulphas,  003 
Zingiber,  62 
Zygadenus,  430 


,j 


M 


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ji^ii^iiQgy 

Liibjrsiiry 

/VOy  IX  ,93^ 

NOV  28  19:^'> 
DEC   12  1932 

°^^     8  1940 

TEB  14  1933 

■  ;,* 

DEC  16  1940 

I    2V)1P^4 

OCT  22  1941 

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d 

NOV  18  193P 
DEC  2  8  1939 

OEC  8     1941 

tWW^   9:-  1947 

LD  'Jl-riOmS,  32 

■ps/?- 

CI 

UNIVERSITY  OF  CALIFORNIA  UBRARY 


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